Basics of Genetics

Basics of Genetics University level genetics

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Contents Articles Basics of genetics

1

Introduction to genetics

1

Gene

7

Allele

18

Chromosome

20

Autosome

30

Ploidy

31

Zygosity

35

Phenotype

38

Genotype

41

Meiosis

43

Mendelian inheritance

55

Punnett square

60

Dominance

62

Codominance

70

Genetics in Depth

71

Chromosomal crossover

71

Genetic recombination

74

Recombinant DNA

76

Single-nucleotide polymorphism

81

Epigenetics

86

Aneuploidy

100

Genetic linkage

105

Polymorphism

109

Sex-linkage

130

X chromosome

130

Y chromosome

133

Mosaic

140

SRY

143

Barr body

149

Sex linkage

151

Dosage compensation

Genetic disorders

154 155

Phenylketonuria

155

Trisomy

161

Chromosome abnormality

163

Chromosomal translocation

165

X-inactivation

168

Genetic disorder

173

Fragile X syndrome

177

Chimerism

185

Turner syndrome

191

Down syndrome

200

Edwards syndrome

215

Patau syndrome

218

Cat eye syndrome

222

Cri du chat

224

Klinefelter's syndrome

227

Androgen insensitivity syndrome

232

XX male syndrome

245

XY gonadal dysgenesis

247

Tay–Sachs disease

250

Interesting Information

258

CSI effect

258

ABO blood group system

263

Hh antigen system

275

References Article Sources and Contributors

279

Image Sources, Licenses and Contributors

288

Article Licenses License

292

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Basics of genetics Introduction to genetics Part of a series on

Genetics Key components •

Chromosome

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DNA

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RNA

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Genome

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Heredity

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Mutation

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Nucleotide

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Variation

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Glossary Index Outline History and topics

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Introduction History

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Evolution (molecular)

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Population genetics

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Mendelian inheritance

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Quantitative genetics

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Molecular genetics Research

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DNA sequencing

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Genetic engineering

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Genomics (

template)

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Medical genetics

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Branches of genetics Biology portal

Genetics is the study of genes, and studies what genes are and how they work. Genes are how living organisms inherit features from their ancestors; for example, children usually look like their parents because they have inherited their parents' genes. Genetics tries to identify which features are inherited, and explain how these features pass from generation to generation. In genetics, a feature of a living thing is called a "trait". Some traits are part of an organism's physical appearance; such as a person's eye-color, height or weight. Other sorts of traits are not easily seen and include blood types or resistance to diseases. The way our genes and environment interact to produce a trait can be complicated. For example, the chances of somebody dying of cancer or heart disease seems to depend on both their genes and their

Introduction to genetics

2

lifestyle. Genes are made from a long molecule called DNA, which is copied and inherited across generations. DNA is made of simple units that line up in a particular order within this large molecule. The order of these units carries genetic information, similar to how the order of letters on a page carries information. The language used by DNA is called the genetic code, which allows the genetic machinery to read the information in the genes in triplet sets of codons. This information is the instructions for constructing and operating a living organism. The information within a particular gene is not always exactly the same between one organism and another, so different copies of a gene do not always give exactly the same instructions. Each unique form of a single gene is called an allele. As an example, one allele for the gene for hair color could instruct the body to produce a lot of pigment, producing black hair, while a different allele of the same gene might give garbled instructions that fail to produce any pigment, giving white hair. Mutations are random changes in genes, and can create new alleles. Mutations can also produce new traits, such as when mutations to an allele for black hair produce a new allele for white hair. This appearance of new traits is important in evolution.

Inheritance in biology Genes and inheritance Genes are inherited as units, with two parents dividing out copies of their genes to their offspring. You can think of this process as like mixing two hands of cards, shuffling them, and then dealing them out again. Humans have two copies of each of their genes, and make copies that they put into eggs or sperm—but they only include one copy of each type of gene. An egg and sperm join to form a complete set of genes. The eventually resulting child has the same number of genes as their parents, but for any gene one of their two copies comes from their father, and one from their mother.[]

A section of DNA; the sequence of the plate-like units (nucleotides) in the center carries information.

The effects of this mixing depend on the types (the alleles) of the gene. If the father has two copies of an allele for red hair, and the mother has two copies for brown hair, all their children get the two alleles that give different instructions, one for red hair and one for brown. The hair color of these children depends on how these alleles work together. If one allele overrides the instructions from another, it is called the dominant allele, and the allele that is overridden is called the recessive allele. In the case of a daughter with alleles for both red and brown hair, brown is dominant and she ends up with brown hair.[1]

Although the red color allele is still there in this brown-haired girl, it doesn't show. This is a difference between what you see on the surface (the traits of an organism, called its phenotype) and the genes within the organism (its genotype). In this example you can call the allele for brown "B" and the allele for red "b". (It is normal to write dominant alleles with capital letters and recessive ones with lower-case letters.) The brown hair daughter has the "brown hair phenotype" but her genotype is Bb, with one copy of the B allele, and one of the b allele.

Introduction to genetics

3 Now imagine that this woman grows up and has children with a brown hair man who also has a Bb genotype. Her eggs will be a mixture of two types, one sort containing the B allele, and one sort the b allele. Similarly, her partner will produce a mix of two types of sperm containing one or the other of these two alleles. When the transmitted genes are joined up in their offspring, these children have a chance of getting either brown or red hair, since they could get a genotype of BB = brown hair, Bb = brown hair or bb = red hair. In this generation, there is therefore a chance of the recessive allele showing itself in the phenotype of the children - some of them may have red hair like their grandfather.[1]

Many traits are inherited in a more complicated way than the example above. This can happen when there are several genes involved, each contributing a small part to the end result. Tall people tend to have tall children because their children get a package of many alleles that each Red hair is a recessive trait. contribute a bit to how much they grow. However, there are not clear groups of "short people" and "tall people", like there are groups of people with brown or red hair. This is because of the large number of genes involved; this makes the trait very variable and people are of many different heights.[2] Despite a common misconception, the green/blue eye traits are also inherited in this complex inheritance model.[3] Inheritance can also be complicated when the trait depends on interaction between genetics and environment. For example, malnutrition does not change traits like eye color, but can stunt growth.[4]

Inherited diseases Some diseases are hereditary and run in families; others, such as infectious diseases, are caused by the environment. Other diseases come from a combination of genes and the environment.[5] Genetic disorders are diseases that are caused by a single allele of a gene and are inherited in families. These include Huntington's disease, Cystic fibrosis or Duchenne muscular dystrophy. Cystic fibrosis, for example, is caused by mutations in a single gene called CFTR and is inherited as a recessive trait.[6] Other diseases are influenced by genetics, but the genes a person gets from their parents only change their risk of getting a disease. Most of these diseases are inherited in a complex way, with either multiple genes involved, or coming from both genes and the environment. As an example, the risk of breast cancer is 50 times higher in the families most at risk, compared to the families least at risk. This variation is probably due to a large number of alleles, each changing the risk a little bit.[7] Several of the genes have been identified, such as BRCA1 and BRCA2, but not all of them. However, although some of the risk is genetic, the risk of this cancer is also increased by being overweight, drinking a lot of alcohol and not exercising.[8] A woman's risk of breast cancer therefore comes from a large number of alleles interacting with her environment, so it is very hard to predict.

How genes work Genes make proteins The function of genes is to provide the information needed to make molecules called proteins in cells.[] Cells are the smallest independent parts of organisms: the human body contains about 100 trillion cells, while very small organisms like bacteria are just one single cell. A cell is like a miniature and very complex factory that can make all the parts needed to produce a copy of itself, which happens when cells divide. There is a simple division of labor in cells - genes give instructions and proteins carry out these instructions, tasks like building a new copy of a cell, or

Introduction to genetics repairing damage.[9] Each type of protein is a specialist that only does one job, so if a cell needs to do something new, it must make a new protein to do this job. Similarly, if a cell needs to do something faster or slower than before, it makes more or less of the protein responsible. Genes tell cells what to do by telling them which proteins to make and in what amounts. Proteins are made of a chain of 20 different types of amino acid molecules. This chain folds up into a compact shape, rather like an untidy ball of string. The shape of the protein is determined by the sequence of amino acids along its chain and it is this shape that, in turn, determines what the protein does.[9] For Genes are expressed by being transcribed into RNA, and this RNA then example, some proteins have parts of their translated into protein. surface that perfectly match the shape of another molecule, allowing the protein to bind to this molecule very tightly. Other proteins are enzymes, which are like tiny machines that alter other molecules.[10] The information in DNA is held in the sequence of the repeating units along the DNA chain.[11] These units are four types of nucleotides (A,T,G and C) and the sequence of nucleotides stores information in an alphabet called the genetic code. When a gene is read by a cell the DNA sequence is copied into a very similar molecule called RNA (this process is called transcription). Transcription is controlled by other DNA sequences (such as promoters), which show a cell where genes are, and control how often they are copied. The RNA copy made from a gene is then fed through a structure called a ribosome, which translates the sequence of nucleotides in the RNA into the correct sequence of amino acids and joins these amino acids together to make a complete protein chain. The new protein then folds up into its active form. The process of moving information from the language of RNA into the language of amino acids is called translation.[12]

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Introduction to genetics

5 If the sequence of the nucleotides in a gene changes, the sequence of the amino acids in the protein it produces may also change - if part of a gene is deleted, the protein produced is shorter and may not work any more.[9] This is the reason why different alleles of a gene can have different effects in an organism. As an example, hair color depends on how much of a dark substance called melanin is put into the hair as it grows. If a person has a normal set of the genes involved in making melanin, they make all the proteins needed and they grow dark hair. However, if the alleles for a particular protein have different sequences and produce proteins that can't do their jobs, no melanin is produced and the person has white skin and hair (albinism).[13]

Genes are copied Genes are copied each time a cell divides into two new cells. The process that copies DNA is called DNA replication.[11] It is through a similar process that a child inherits genes from its parents, when a copy from the mother is mixed with a copy from the father.

DNA replication. DNA is unwound and nucleotides are matched to make two new strands.

DNA can be copied very easily and accurately because each piece of DNA can direct the creation of a new copy of its information. This is because DNA is made of two strands that pair together like the two sides of a zipper. The nucleotides are in the center, like the teeth in the zipper, and pair up to hold the two strands together. Importantly, the four different sorts of nucleotides are different shapes, so for the strands to close up properly, an A nucleotide must go opposite a T nucleotide, and a G opposite a C. This exact pairing is called base

pairing.[11] When DNA is copied, the two strands of the old DNA are pulled apart by enzymes that move along each of the two single strands pairing up new nucleotide units and then zipping the strands closed. This produces two new pieces of DNA, each containing one strand from the old DNA and one newly made strand. This process isn't perfect and sometimes the proteins make mistakes and put the wrong nucleotide into the strand they are building. This causes a change in the sequence of that gene. These changes in DNA sequence are called mutations.[14] Mutations produce new alleles of genes. Sometimes these changes stop the gene from working properly, like the melanin genes discussed above. In other cases these mutations can change what the gene does or even let it do its job a little better than before. These mutations and their effects on the traits of organisms are one of the causes of evolution.[]

Genes and evolution A population of organisms evolves when an inherited trait becomes more common or less common over time.[] For instance, all the mice living on an island would be a single population of mice. If over a few generations, white mice went from being rare, to being a large part of this population, then the coat color of these mice would be evolving. In terms of genetics, this is called a change in allele frequency—such as an increase in the frequency of the allele for white fur.

Mice with different coat colors.

Introduction to genetics Alleles become more or less common either just by chance (in a process called genetic drift), or through natural selection.[15] In natural selection, if an allele makes it more likely for an organism to survive and reproduce, then over time this allele becomes more common. But if an allele is harmful, natural selection makes it less common. For example, if the island was getting colder each year and was covered with snow for much of the time, then the allele for white fur would become useful for the mice, since it would make them harder to see against the snow. Fewer of the white mice would be eaten by predators, so over time white mice would out-compete mice with dark fur. White fur alleles would become more common, and dark fur alleles would become more rare. Mutations create new alleles. These alleles have new DNA sequences and can produce proteins with new properties.[16] So if an island was populated entirely by black mice, mutations could happen creating alleles for white fur. The combination of mutations creating new alleles at random, and natural selection picking out those that are useful, causes adaptation. This is when organisms change in ways that help them to survive and reproduce.

Genetic engineering Since traits come from the genes in a cell, putting a new piece of DNA into a cell can produce a new trait. This is how genetic engineering works. For example, rice can be given genes from a maize and a soil bacteria so the rice produces beta-carotene, which the body converts to Vitamin A.[17] This can help children suffering from Vitamin A deficiency. Other genes that can be put into crops include a natural insecticide from the bacteria Bacillus thuringiensis. The insecticide kills insects that eat the plants, but is harmless to people.[18] In these plants, the new genes are put into the plant before it is grown, so the genes are in every part of the plant, including its seeds.[19] The plant's offspring inherit the new genes, which has led to concern about the spread of new traits into wild plants.[20] The kind of technology used in genetic engineering is also being developed to treat people with genetic disorders in an experimental medical technique called gene therapy.[21] However, here the new gene is put in after the person has grown up and become ill, so any new gene is not inherited by their children. Gene therapy works by trying to replace the allele that causes the disease with an allele that works properly.

References [1] MELANOCORTIN 1 RECEPTOR (http:/ / www. ncbi. nlm. nih. gov/ omim/ 155555), Accessed 27 November 2010 [2] Multifactorial Inheritance (http:/ / www. childrensnyp. org/ mschony/ P02134. html) Health Library, Morgan Stanley Children's Hospital, Accessed 20 May 2008 [3] Eye color is more complex than two genes (http:/ / www. athro. com/ evo/ gen/ inherit1. html#uncertainty), Athro Limited, Accessed 27 November 2010 [5] requently Asked Questions About Genetic Disorders (http:/ / www. genome. gov/ 19016930) NIH, Accessed 20 May 2008 [6] Cystic fibrosis (http:/ / ghr. nlm. nih. gov/ condition=cysticfibrosis) Genetics Home Reference, NIH, Accessed 16 May 2008 [8] What Are the Risk Factors for Breast Cancer? (http:/ / www. cancer. org/ docroot/ CRI/ content/ CRI_2_4_2X_What_are_the_risk_factors_for_breast_cancer_5. asp) American Cancer Society, Accessed 16 May 2008 [9] The Structures of Life (http:/ / publications. nigms. nih. gov/ structlife/ chapter1. html) National Institute of General Medical Sciences, Accessed 20th May 2008 [10] Enzymes (http:/ / www. howstuffworks. com/ cell2. htm) HowStuffWorks, Accessed 20th May 2008 [11] What is DNA? (http:/ / ghr. nlm. nih. gov/ handbook/ basics/ dna) Genetics Home Reference, Accessed 16 May 2008 [12] DNA-RNA-Protein (http:/ / nobelprize. org/ educational_games/ medicine/ dna/ index. html) Nobelprize.org, Accessed 20th May 2008 [13] What is Albinism? (http:/ / www. albinism. org/ publications/ what_is_albinism. html) The National Organization for Albinism and Hypopigmentation, Accessed 20 May 2008 [14] Mutations (http:/ / learn. genetics. utah. edu/ units/ disorders/ mutations/ ) The University of Utah, Genetic Science Learning Center, Accessed 20th May 2008 [15] Mechanisms: The Processes of Evolution (http:/ / evolution. berkeley. edu/ evosite/ evo101/ IIIMechanisms. shtml) Understanding Evolution, Accessed 20th May 2008 [16] Genetic Variation (http:/ / evolution. berkeley. edu/ evosite/ evo101/ IIICGeneticvariation. shtml) Understanding Evolution, Accessed 20th May 2008 [17] Staff Golden Rice Project (http:/ / www. goldenrice. org/ ) Retrieved 5 November 2012 [18] Tifton, Georgia: A Peanut Pest Showdown (http:/ / ars. usda. gov/ is/ ar/ archive/ nov99/ pest1199. htm) USDA, accessed 16 May 2008

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[19] Genetic engineering: Bacterial arsenal to combat chewing insects (http:/ / www. gmo-safety. eu/ basic-info/ 129. bacterial-arsenal-combat-chewing-insects. html) GMO Safety, Jul 2010 [20] Genetically engineered organisms public issues education (http:/ / www. geo-pie. cornell. edu/ gmo. html) Cornell University, Accessed 16 May 2008

External links • • • • • • • •

Introduction to Genetics (http://learn.genetics.utah.edu/), University of Utah Introduction to Genes and Disease (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=gnd), NCBI open book Genetics glossary (http://www.genome.gov/glossary/), A talking glossary of genetic terms. Animated guide to cloning (http://www.blackwellpublishing.com/trun/artwork/Animations/cloningexp/ cloningexp.html) Genetics (http://www.ncbi.nlm.nih.gov/About/primer/genetics.html) NCBI, A Science Primer Khan Academy on YouTube (http://www.youtube.com/user/khanacademy#p/c/7A9646BC5110CF64/5/ _-vZ_g7K6P0) What Color Eyes Would Your Children Have? (http://museum.thetech.org/ugenetics/eyeCalc/eyecalculator. html) Genetics of human eye color: An interactive introduction Double Helix Game (http://nobelprize.org/educational_games/medicine/dna_double_helix/index.html) from the Nobel Prize website. Match CATG bases with each other, and other games

• Transcribe and translate a gene (http://learn.genetics.utah.edu/units/basics/transcribe/), University of Utah • StarGenetics (http://web.mit.edu/star/genetics/) software simulates mating experiments between organisms that are genetically different across a range of traits

Gene A gene is a molecular unit of heredity of a living organism. It is widely accepted by the scientific community as a name given to some stretches of DNA and RNA that code for a polypeptide or for an RNA chain that has a function in the organism, though there still are controversies about what plays the role of the genetic material.[1] Living beings depend on genes, as they specify all proteins and functional RNA chains. Genes hold the information to build and maintain an organism's cells and pass genetic traits to offspring. All organisms have many genes corresponding to various biological traits, some of which are immediately visible, such as eye color or number of limbs, and some of which are not, such as blood type, increased risk for specific diseases, or the thousands of basic biochemical processes that comprise life.[citation needed]

This stylistic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). The chromosome is X-shaped because it is dividing. Introns are regions often found in eukaryote genes that are removed in the splicing process (after the DNA is transcribed into RNA): Only the exons encode the protein. This diagram labels a region of only 50 or so bases as a gene. In reality, most genes are hundreds of times larger.

Gene

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A modern working definition of a gene is "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions ".[][] Colloquial usage of the term gene (e.g. "good genes", "hair color gene") may actually refer to an allele: a gene is the basic instruction—a sequence of nucleic acids (DNA or, in the case of certain viruses RNA), while an allele is one variant of that gene. Thus, when the mainstream press refers to "having" a "gene" for a specific trait, this is generally inaccurate. In most cases, all people would have a gene for the trait in question, but certain people will have a specific allele of that gene, which results in the trait variant. Further, genes code for proteins, which might result in identifiable traits, but it is the gene, not the trait, which is inherited. The chemical structure of a four-base fragment of a DNA double helix.

Physical definitions RNA genes and genomes When proteins are manufactured, the gene is first copied into RNA as an intermediate product. In other cases, the RNA molecules are the actual functional products. For example, RNAs known as ribozymes are capable of enzymatic function, and microRNA has a regulatory role. The DNA sequences from which such RNAs are transcribed are known as RNA genes. Some viruses store their entire genomes in the form of RNA, and contain no DNA at all. Because they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription. On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized. In 2006, French researchers came across a puzzling example of RNA-mediated inheritance in mice. Mice with a loss-of-function mutation in the gene Kit have white tails. Offspring of these mutants can have white tails despite having only normal Kit genes. The research team traced this effect back to mutated Kit RNA.[] While RNA is common as genetic storage material in viruses, in mammals in particular RNA inheritance has been observed very rarely.

Gene

Functional structure of a gene The vast majority of living organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar (2'-deoxyribose), a phosphate group, and one of the four bases adenine, cytosine, guanine, and thymine. The most common form of DNA in a cell is in a double helix structure, in which two individual DNA strands twist around each other in a right-handed spiral. In this structure, the base pairing rules specify that guanine pairs with cytosine and adenine pairs with thymine. The base pairing between Diagram of the "typical" eukaryotic protein-coding gene. Promoters and enhancers guanine and cytosine forms three determine what portions of the DNA will be transcribed into the precursor mRNA hydrogen bonds, whereas the base (pre-mRNA). The pre-mRNA is then spliced into messenger RNA (mRNA) which is later pairing between adenine and thymine translated into protein. forms two hydrogen bonds. The two strands in a double helix must therefore be complementary, that is, their bases must align such that the adenines of one strand are paired with the thymines of the other strand, and so on. Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end. The directionality of DNA is vitally important to many cellular processes, since double helices are necessarily directional (a strand running 5'-3' pairs with a complementary strand running 3'-5'), and processes such as DNA replication occur in only one direction. All nucleic acid synthesis in a cell occurs in the 5'-3' direction, because new monomers are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile. The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three-nucleotide sequences called codons, which serve as the words in the genetic language. The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms. All genes have regulatory regions in addition to regions that explicitly code for a protein or RNA product. A regulatory region shared by almost all genes is known as the promoter, which provides a position that is recognized by the transcription machinery when a gene is about to be transcribed and expressed. A gene can have more than one promoter, resulting in RNAs that differ in how far they extend in the 5' end.[2] Although promoter regions have a consensus sequence that is the most common sequence at this position, some genes have "strong" promoters that bind the transcription machinery well, and others have "weak" promoters that bind poorly. These weak promoters usually permit a lower rate of transcription than the strong promoters, because the transcription machinery binds to

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Gene them and initiates transcription less frequently. Other possible regulatory regions include enhancers, which can compensate for a weak promoter. Most regulatory regions are "upstream"—that is, before or toward the 5' end of the transcription initiation site. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters. Many prokaryotic genes are organized into operons, or groups of genes whose products have related functions and which are transcribed as a unit. By contrast, eukaryotic genes are transcribed only one at a time, but may include long stretches of DNA called introns which are transcribed but never translated into protein (they are spliced out before translation). Splicing can also occur in prokaryotic genes, but is less common than in eukaryotes.[3]

Chromosomes The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes; the region of the chromosome at which a particular gene is located is called its locus. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. Prokaryotes—bacteria and archaea—typically store their genomes on a single large, circular chromosome, sometimes supplemented by additional small circles of DNA called plasmids, which usually encode only a few genes and are easily transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer. Although some simple eukaryotes also possess plasmids with small numbers of genes, the majority of eukaryotic genes are stored on multiple linear chromosomes, which are packed within the nucleus in complex with storage proteins called histones. The manner in which DNA is stored on the histone, as well as chemical modifications of the histone itself, are regulatory mechanisms governing whether a particular region of DNA is accessible for gene expression. The ends of eukaryotic chromosomes are capped by long stretches of repetitive sequences called telomeres, which do not code for any gene product but are present to prevent degradation of coding and regulatory regions during DNA replication. The length of the telomeres tends to decrease each time the genome is replicated in preparation for cell division; the loss of telomeres has been proposed as an explanation for cellular senescence, or the loss of the ability to divide, and by extension for the aging process in organisms.[] Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain so-called "junk DNA", or regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas the genomes of complex multicellular organisms, including humans, contain an absolute majority of DNA without an identified function.[] However it now appears that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer.[]

Gene expression In all organisms, there are two major steps separating a protein-coding gene from its protein: First, the DNA on which the gene resides must be transcribed from DNA to messenger RNA (mRNA); and, second, it must be translated from mRNA to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression, and the resulting molecule itself is called a gene product.

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Genetic code The genetic code is the set of chemical symbols by which a gene is translated into a functional protein. Each gene consists of a specific sequence of nucleotides encoded in a DNA (or sometimes RNA in some viruses[4]) strand; a correspondence between nucleotides, the basic building blocks of genetic material, and amino acids, the basic building blocks of proteins, must be established for genes to be successfully translated into functional proteins. Sets of three nucleotides, known as codons, each correspond to a specific amino acid or to a signal; three codons are known as "stop codons" and, instead of specifying a new amino acid, alert the translation machinery that the end of the gene has been reached. There are 64 possible codons (four possible nucleotides at each of three positions, hence 43 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms.

Schematic diagram of a single-stranded RNA molecule illustrating the position of three-base codons.

Transcription The process of genetic transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed. The DNA strand whose sequence matches that of the RNA is known as the coding strand and the strand from which the RNA was synthesized is the template strand. Transcription is performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5' direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first recognizes and binds a promoter region of the gene. Thus a major mechanism of gene regulation is the blocking or sequestering of the promoter region, either by tight binding by repressor molecules that physically block the polymerase, or by organizing the DNA so that the promoter region is not accessible. In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may begin at the 5' end of the RNA while the 3' end is still being transcribed. In eukaryotes, transcription necessarily occurs in the nucleus, where the cell's DNA is sequestered; the RNA molecule produced by the polymerase is known as the primary transcript and must undergo post-transcriptional modifications before being exported to the cytoplasm for translation. The splicing of introns present within the transcribed region is a modification unique to eukaryotes; alternative splicing mechanisms can result in mature transcripts from the same gene having different sequences and thus coding for different proteins. This is a major form of regulation in eukaryotic cells.

Translation Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein. Translation is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new amino acids to a growing polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to the codon it reads; the tRNA is also covalently attached to the amino acid specified by the complementary codon. When the tRNA binds to its complementary codon in an mRNA strand, the ribosome ligates its amino acid cargo to the new polypeptide chain, which is synthesized from amino terminus to carboxyl terminus.

Gene During and after its synthesis, the new protein must fold to its active three-dimensional structure before it can carry out its cellular function.

DNA replication and inheritance The growth, development, and reproduction of organisms relies on cell division, or the process by which a single cell divides into two usually identical daughter cells. This requires first making a duplicate copy of every gene in the genome in a process called DNA replication. The copies are made by specialized enzymes known as DNA polymerases, which "read" one strand of the double-helical DNA, known as the template strand, and synthesize a new complementary strand. Because the DNA double helix is held together by base pairing, the sequence of one strand completely specifies the sequence of its complement; hence only one strand needs to be read by the enzyme to produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.[] After DNA replication is complete, the cell must physically separate the two copies of the genome and divide into two distinct membrane-bound cells. In prokaryotes - bacteria and archaea - this usually occurs via a relatively simple process called binary fission, in which each circular genome attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S phase, whereas the process of segregating chromosomes and splitting the cytoplasm occurs during M phase. In many single-celled eukaryotes such as yeast, reproduction by budding is common, which results in asymmetrical portions of cytoplasm in the two daughter cells.

Molecular inheritance The duplication and transmission of genetic material from one generation of cells to the next is the basis for molecular inheritance, and the link between the classical and molecular pictures of genes. Organisms inherit the characteristics of their parents because the cells of the offspring contain copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or contain only one copy of each gene. The gametes produced by females are called eggs or ova, and those produced by males are called sperm. Two gametes fuse to form a fertilized egg, a single cell that once again has a diploid number of genes—each with one copy from the mother and one copy from the father. During the process of meiotic cell division, an event called genetic recombination or crossing-over can sometimes occur, in which a length of DNA on one chromatid is swapped with a length of DNA on the corresponding sister chromatid. This has no effect if the alleles on the chromatids are the same, but results in reassortment of otherwise linked alleles if they are different. The Mendelian principle of independent assortment asserts that each of a parent's two genes for each trait will sort independently into gametes; which allele an organism inherits for one trait is unrelated to which allele it inherits for another trait. This is in fact only true for genes that do not reside on the same chromosome, or are located very far from one another on the same chromosome. The closer two genes lie on the same chromosome, the more closely they will be associated in gametes and the more often they will appear together; genes that are very close are essentially never separated because it is extremely unlikely that a crossover point will occur between them. This is known as genetic linkage.

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Gene

13

History The notion of a gene[5] is evolving with the science of genetics, which began when Gregor Mendel noticed that biological variations are inherited from parent organisms as specific, discrete traits. The biological entity responsible for defining traits was later termed a gene, but the biological basis for inheritance remained unknown until DNA was identified as the genetic material in the 1940s. Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, which proposes that the traits of the parents blend or mix in a smooth, continuous gradient in the offspring. Although Mendel's work was largely unrecognized after its first publication in 1866, it was rediscovered in 1900 by three European scientists, Hugo de Vries, Carl Correns, and Erich von Tschermak, who had reached similar conclusions from their own research. However, these scientists were not yet aware of the identity of the 'discrete units' on which genetic material resides.

Gregor Mendel

The existence of genes was first suggested by Gregor Mendel (1822–1884), who, in the 1860s, studied inheritance in peaplants (Pisum sativum) and hypothesized a factor that conveys traits from parent to offspring. He spent over 10 years of his life on one experiment. Although he did not use the term gene, he explained his results in terms of inherited characteristics. Mendel was also the first to hypothesize independent assortment, the distinction between dominant and recessive traits, the distinction between a heterozygote and homozygote, and the difference between what would later be described as genotype (the genetic material of an organism) and phenotype (the visible traits of that organism). Charles Darwin used the term Gemmule to describe a microscopic unit of inheritance, and what would later become known as chromosomes had been observed separating out during cell division by Wilhelm Hofmeister as early as 1848. The idea that chromosomes are the carriers of inheritance was expressed in 1883 by Wilhelm Roux. Darwin also coined the word pangenesis by (1868).[6] The word pangenesis is made from the Greek words pan (a prefix meaning "whole", "encompassing") and genesis ("birth") or genos ("origin"). Mendel's concept was given a name by Hugo de Vries in 1889, in his book Intracellular Pangenesis; although probably unaware of Mendel's work at the time, he coined the term "pangen" for "the smallest particle [representing] one hereditary characteristic".[7] Danish botanist Wilhelm Johannsen coined the word "gene" ("gen" in Danish and German) in 1909 to describe the fundamental physical and functional units of heredity,[] while the related word genetics was first used by William Bateson in 1905.[] He derived the word from de Vries' "pangen". In the early 1900s, Mendel's work received renewed attention from scientists. In 1910, Thomas Hunt Morgan showed that genes reside on specific chromosomes. He later showed that genes occupy specific locations on the chromosome. With this knowledge, Morgan and his students began the first chromosomal map of the fruit fly Drosophila. In 1928, Frederick Griffith showed that genes could be transferred. In what is now known as Griffith's experiment, injections into a mouse of a deadly strain of bacteria that had been heat-killed transferred genetic information to a safe strain of the same bacteria, killing the mouse. A series of subsequent discoveries led to the realization decades later that chromosomes within cells are the carriers of genetic material, and that they are made of DNA (deoxyribonucleic acid), a polymeric molecule found in all cells on which the 'discrete units' of Mendelian inheritance are encoded. In 1941, George Wells Beadle and Edward Lawrie Tatum showed that mutations in genes caused errors in specific steps in metabolic pathways. This showed that specific genes code for specific proteins, leading to the "one gene, one enzyme" hypothesis.[] Oswald Avery, Colin Munro MacLeod, and Maclyn McCarty showed in 1944 that DNA holds the gene's information.[8] In 1953,

Gene James D. Watson and Francis Crick demonstrated the molecular structure of DNA. Together, these discoveries established the central dogma of molecular biology, which states that proteins are translated from RNA which is transcribed from DNA. This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses. In 1972, Walter Fiers and his team at the Laboratory of Molecular Biology of the University of Ghent (Ghent, Belgium) were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.[] Richard J. Roberts and Phillip Sharp discovered in 1977 that genes can be split into segments. This led to the idea that one gene can make several proteins. Recently (as of 2003–2006), biological results let the notion of gene appear more slippery. In particular, genes do not seem to sit side by side on DNA like discrete beads. Instead, regions of the DNA producing distinct proteins may overlap, so that the idea emerges that "genes are one long continuum".[] It was first hypothesized in 1986 by Walter Gilbert that neither DNA nor protein would be required in such a primitive system as that of a very early stage of the earth if RNA could perform as simply a catalyst and genetic information storage processor. The modern study of genetics at the level of DNA is known as molecular genetics and the synthesis of molecular genetics with traditional Darwinian evolution is known as the modern evolutionary synthesis.

Mendelian inheritance and classical genetics According to the theory of Mendelian inheritance, variations in phenotype—the observable physical and behavioral characteristics of an organism—are due in part to variations in genotype, or the organism's particular set of genes, each of which specifies a particular trait. Different forms of a gene, which may give rise to different phenotypes, are known as alleles. Organisms such as the pea plants Mendel worked on, along with many plants and animals, have two alleles for each trait, one inherited from each parent. Alleles may be dominant or recessive; dominant alleles give rise to their corresponding phenotypes when paired with any other allele for the same trait, whereas recessive alleles give rise to their corresponding phenotype only when paired with another copy of the same allele. For example, if Crossing between two pea plants heterozygous the allele specifying tall stems in pea plants is dominant over the allele for purple (B, dominant) and white (b, recessive) blossoms specifying short stems, then pea plants that inherit one tall allele from one parent and one short allele from the other parent will also have tall stems. Mendel's work demonstrated that alleles assort independently in the production of gametes, or germ cells, ensuring variation in the next generation.

Mutation DNA replication is for the most part extremely accurate, with an error rate per site of around 10−6 to 10−10 in eukaryotes.[] (Although in prokaryotes and viruses, the rate is much higher.) Rare, spontaneous alterations in the base sequence of a particular gene arise from a number of sources, such as errors in DNA replication and the aftermath of DNA damage. These errors are called mutations. The cell contains many DNA repair mechanisms for preventing mutations and maintaining the integrity of the genome; however, in some cases—such as breaks in both DNA strands of a chromosome—repairing the physical damage to the molecule is a higher priority than producing an exact copy. Due to the degeneracy of the genetic code, some mutations in protein-coding genes are silent, or produce no change in the amino acid sequence of the protein for which they code; for example, the codons UCU and UUC both code for serine, so the U↔C mutation has no effect on the protein. Mutations that do have phenotypic

14

Gene effects are most often neutral or deleterious to the organism, but sometimes they confer benefits to the organism's fitness. Mutations propagated to the next generation lead to variations within a species' population. Variants of a single gene are known as alleles, and differences in alleles may give rise to differences in traits. Although it is rare for the variants in a single gene to have clearly distinguishable phenotypic effects, certain well-defined traits are in fact controlled by single genetic loci. A gene's most common allele is called the wild type allele, and rare alleles are called mutants. However, this does not imply that the wild-type allele is the ancestor from which the mutants are descended.

Genome Chromosomal organization The total complement of genes in an organism or cell is known as its genome. In prokaryotes, the vast majority of genes are located on a single chromosome of circular DNA, while eukaryotes usually possess multiple individual linear DNA helices packed into dense DNA-protein complexes called chromosomes. Genes that appear together on one chromosome of one species may appear on separate chromosomes in another species. Many species carry more than one copy of their genome within each of their somatic cells. Cells or organisms with only one copy of each chromosome are called haploid; those with two copies are called diploid; and those with more than two copies are called polyploid. The copies of genes on the chromosomes are not necessarily identical. In sexually reproducing organisms, one copy is normally inherited from each parent.

Number of genes Early estimates of the number of human genes that used expressed sequence tag data put it at 50 000–100 000.[10] Following the sequencing of the human genome and other genomes, it has been found that rather few genes (~20 000 in human, mouse and fly, ~13 000 in roundworm, >46,000 in rice[]) encode all the proteins in an The human genome, categorized by function of each gene product, given both as number organism.[] These protein-coding [9] of genes and as percentage of all genes. sequences make up 1–2% of the human genome.[] A large part of the genome is transcribed however, to introns, retrotransposons and seemingly a large array of noncoding RNAs.[][] Total number of proteins (the Earth's proteome) is estimated to be 5 million sequences.[11]

Genetic and genomic nomenclature Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC) for each known human gene in the form of an approved gene name and symbol (short-form abbreviation). All approved symbols are stored in the HGNC Database [12]. Each symbol is unique and each gene is only given one approved gene symbol. This also facilitates electronic data retrieval from publications. In preference each symbol maintains parallel construction in different members of a gene family and can be used in other species, especially the mouse.

15

Gene

Evolutionary concept of a gene George C. Williams first explicitly advocated the gene-centric view of evolution in his 1966 book Adaptation and Natural Selection. He proposed an evolutionary concept of gene to be used when we are talking about natural selection favoring some genes. The definition is: "that which segregates and recombines with appreciable frequency." According to this definition, even an asexual genome could be considered a gene, insofar that it have an appreciable permanency through many generations. The difference is: the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit. Richard Dawkins' books The Selfish Gene (1976) and The Extended Phenotype (1982) defended the idea that the gene is the only replicator in living systems. This means that only genes transmit their structure largely intact and are potentially immortal in the form of copies. So, genes should be the unit of selection. In The Selfish Gene Dawkins attempts to redefine the word 'gene' to mean "an inheritable unit" instead of the generally accepted definition of "a section of DNA coding for a particular protein". In River Out of Eden, Dawkins further refined the idea of gene-centric selection by describing life as a river of compatible genes flowing through geological time. Scoop up a bucket of genes from the river of genes, and we have an organism serving as temporary bodies or survival machines. A river of genes may fork into two branches representing two non-interbreeding species as a result of geographical separation.

Gene targeting and implications Gene targeting is commonly referred to techniques for altering or disrupting mouse genes and provides the mouse models for studying the roles of individual genes in embryonic development, human disorders, aging and diseases. The mouse models, where one or more of its genes are deactivated or made inoperable, are called knockout mice. Since the first reports in which homologous recombination in embryonic stem cells was used to generate gene-targeted mice,[13] gene targeting has proven to be a powerful means of precisely manipulating the mammalian genome, producing at least ten thousand mutant mouse strains and it is now possible to introduce mutations that can be activated at specific time points, or in specific cells or organs, both during development and in the adult animal.[14][15] Gene targeting strategies have been expanded to all kinds of modifications, including point mutations, isoform deletions, mutant allele correction, large pieces of chromosomal DNA insertion and deletion, tissue specific disruption combined with spatial and temporal regulation and so on. It is predicted that the ability to generate mouse models with predictable phenotypes will have a major impact on studies of all phases of development, immunology, neurobiology, oncology, physiology, metabolism, and human diseases. Gene targeting is also in theory applicable to species from which totipotent embryonic stem cells can be established, and therefore may offer a potential to the improvement of domestic animals and plants.[15][16]

Changing concept The concept of the gene has changed considerably (see history section). From the original definition of a "unit of inheritance", the term evolved to mean a DNA-based unit that can exert its effects on the organism through RNA or protein products. It was also previously believed that one gene makes one protein; this concept was overthrown by the discovery of alternative splicing and trans-splicing.[] The definition of a gene is still changing. The first cases of RNA-based inheritance have been discovered in mammals.[] Evidence is also accumulating that the control regions of a gene do not necessarily have to be close to the coding sequence on the linear molecule or even on the same chromosome. Spilianakis and colleagues discovered that the promoter region of the interferon-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11 come into close proximity in the nucleus possibly to be jointly regulated.[17] Even the coding sequence of a gene itself doesn't have to be all on the same chromosome: Marande and Burger showed

16

Gene that, in the mitochondria of the protist Diplonema papillatum, "genes are systematically fragmented into small pieces that are encoded on separate chromosomes, transcribed individually, and then concatenated into contiguous messenger RNA molecules".[18] The concept that genes are clearly delimited is also being eroded. There is evidence for fused proteins stemming from two adjacent genes that can produce two separate protein products. While it is not clear whether these fusion proteins are functional, the phenomenon is more frequent than previously thought.[19] Even more ground-breaking than the discovery of fused genes is the observation that some proteins can be composed of exons from far away regions and even different chromosomes.[][20] This new data has led to an updated, and probably tentative, definition of a gene as "a union of genomic sequences encoding a coherent set of potentially overlapping functional products".[] This new definition categorizes genes by functional products, whether they be proteins or RNA, rather than specific DNA loci; all regulatory elements of DNA are therefore classified as gene-associated regions.[]

References [1] Sarkar, S. and Plutynski, A. (2008). A Companion to the Philosophy of Biology. Oxford: Blackwell. [4] MeSH (2008) National Library of Medicine - Medical Subject Headings. National library of medicine http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2008/ MB_cgi?mode=& term=RNA+ Viruses& field=entry (accessed 27 September 2011) B04.820. 19990101. [6] Darwin C. (1868). Animals and Plants under Domestication (1868). [7] Vries, H. de (1889) Intracellular Pangenesis (http:/ / www. esp. org/ books/ devries/ pangenesis/ facsimile/ ) ("pangen" definition on page 7 and 40 of this 1910 translation in English) [9] PANTHER Pie Chart (http:/ / www. pantherdb. org/ chart/ summary/ pantherChart. jsp?filterLevel=1& chartType=1& listType=1& type=5& species=Homo sapiens) at the PANTHER Classification System homepage. Retrieved May 25, 2011 [12] http:/ / www. genenames. org/ cgi-bin/ hgnc_search. pl [13] Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell. 1987;51:503-12 [14] The 2007 Nobel Prize in Physiology or Medicine - Press Release (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 2007/ press. html) [15] Deng C. In Celebration of Dr. Mario R. Capecchi's Nobel Prize. Int J Biol Sci 2007; 3:417-419. International Journal of Biological Sciences (http:/ / www. biolsci. org/ v03p0417. htm) [16] Mario R. Capecchi (http:/ / www. hhmi. org/ research/ investigators/ capecchi. html)

Further reading • Dawkins, Richard (1990). The Selfish Gene. Oxford University Press. ISBN 0-19-286092-5. Google Book Search (http://books.google.com/print?id=WkHO9HI7koEC); first published 1976. • Dawkins, Richard (1995). River Out of Eden. Basic Books. ISBN 0-465-06990-8. • Ridley, Matt (1999). Genome: The Autobiography of a Species in 23 Chapters. Fourth Estate. ISBN 0-00-763573-7.

External links • Comparative Toxicogenomics Database (http://ctdbase.org/) • DNA From The Beginning - a primer on genes and DNA (http://www.dnaftb.org/) • Genes And DNA - Introduction to genes and DNA aimed at non-biologist (http://www.bioinformaticstutorials. com/?p=6) • Entrez Gene - a searchable database of genes (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene) • IDconverter - converts gene IDs between public databases (http://idconverter.bioinfo.cnio.es/) • iHOP - Information Hyperlinked over Proteins (http://www.ihop-net.org/UniPub/iHOP/) • TranscriptomeBrowser - Gene expression profile analysis (http://tagc.univ-mrs.fr/tbrowser) • The Protein Naming Utility, a database to identify and correct deficient gene names (http://www.jcvi.org/ pn-utility) • Genes (http://www.mdpi.com/journal/genes/) - an Open Access journal

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Gene • IMPC (International Mouse Phenotyping Consortium) (http://www.mousephenotype.org/) - Encyclopedia of mammalian gene function • Global Genes Project (http://www.globalgenes.org/) - Leading non-profit organization supporting people living with genetic diseases • ENCODE threads Explorer (http://www.nature.com/encode/#/threads/ characterization-of-intergenic-regions-and-gene-definition) Characterization of intergenic regions and gene definition. Nature (journal)

Allele An allele (UK pron.: /ˈæliːl/ or US /əˈliːl/), or allel, is one of a number of alternative forms of the same gene or same genetic locus (generally a group of genes).[][] It is the alternative form of a gene for a character producing different effects. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation. However, many variations at the genetic level result in little or no observable variation. Most multicellular organisms have two sets of chromosomes, that is, they are diploid. These chromosomes are referred to as homologous chromosomes. Diploid organisms have one copy of each gene (and therefore one allele) on each chromosome. If both alleles are the same, they are homozygotes. If the alleles are different, they are heterozygotes. A population or species of organisms typically includes multiple alleles at each locus among various individuals. Allelic variation at a locus is measurable as the number of alleles (polymorphism) present, or the proportion of heterozygotes in the population. For example, at the gene locus for the ABO blood type carbohydrate antigens in humans,5% and may be closer to 7.5%.[citation needed]

Down syndrome

Ultrasound Ultrasound imaging can be used to screen for Down syndrome. Increased fetal nuchal translucency (NT) is an indicator of increased risk of Down syndrome. A 2003 systematic review of 30 studies of NT in Down syndrome found an average sensitivity of 75-80% with a false positive rate of 5.8-6% (95% confidence intervals).[52] Therefore, while the false positive rate is too high for NT to be used alone as a screening test, it is useful as part of a combined test. Ultrasound measurement of NT is usually performed between 11 and 14 weeks gestation. Other ultrasound findings have been associated with Down syndrome. Absence of the fetal nasal bone has been associated with Down syndrome. A 2001 observational study suggested that there is an increased rate of absence of nasal bone in fetuses with Down syndrome.[53] However, it is unclear how useful this would be as a screening test as the reproducibility and consistency of the procedure has not been demonstrated.

Blood tests Several blood markers can be measured that can be used as part of combined tests to predict the risk of Down syndrome. These include α-fetoprotein, β-hCG, inhibin-A, PAPP-A and unconjugated estriol. During the first trimester, a combination of β-hCG and PAPP-A levels can give a 60% detection rate at a 5% false positive rate.[54] In the second trimester, various markers including β-hCG, inhibin-A, α-fetoprotein and unconjugated estriol can be used to give detection rates between 60 and 70%.[55] Several non-invasive prenatal tests which employ DNA sequencing of fragments of fetal DNA in the mother's blood have been developed. Firms include Verinata, acquired by Illumina in January, 2013, Ariosa Diagnostics and Natera.[] MaterniT21 PLUS, introduced by Sequenom in October, 2011,[] detected Down syndrome based on fetal DNA in a sample of the mother's blood in 209 of 212 cases (98.6%).[56] The International Society for Prenatal Diagnosis finds that this is an advanced screening test which may be of use, in conjunction with genetic counseling, in high-risk cases based upon existing screening strategies. While effective in the diagnosis of Down syndrome, it cannot assess other conditions which can be detected by invasive testing; (for pregnant women who are screen-positive using current screening protocols, Down syndrome represents about half of the fetal chromosomal abnormalities identified through amniocentesis and CVS).[57]

Amniocentesis and CVS Where screening tests predict a high risk of the fetus having Down syndrome, more invasive diagnostic tests such as amniocentesis and chorionic villus sampling may be performed. These tests have a much lower false positive rate than the screening tests, therefore they are more reliable in establishing the diagnosis of Down syndrome. However, they are invasive, and carry a slightly increased risk of miscarriage.

Abortion rates A 2002 literature review of elective abortion rates found that 91–93% of pregnancies in the United Kingdom and Europe with a diagnosis of Down syndrome were terminated.[9] Data from the National Down Syndrome Cytogenetic Register in the United Kingdom indicates that from 1989 to 2006 the proportion of women choosing to terminate a pregnancy following prenatal diagnosis of Down syndrome has remained constant at around 92%.[58][59] In the United States a number of studies have examined the abortion rate of fetuses with Down syndrome. Three studies estimated the termination rates at 95%, 98%, and 87% respectively.[9]

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Down syndrome

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Postnatal diagnosis In cases where prenatal tests have been negative or haven't been performed, midwifery staff usually express the initial concern that a newborn has Down's syndrome, such as by distinctive signs or by general appearance.[60] Clinical examination by a pediatrician can often confirm or refute this suspicion with confidence.[60] Systems of diagnostic criteria for such an examination include Fried's diagnostic index, which includes the following 8 signs: flat face, ear dysplasia, tongue protrusion, corners of mouth turned down, hypotonia, neck skin excess, epicanthic fold, and a gap between 1st and 2nd toes.[60] With 0 to 2 of these characteristics the newborn can likely be said to not have Down syndrome (with less than one in 100 false negatives), with 3 to 5 of these characteristics the situation is unclear (and genetic testing is recommended) and with 6 to 8 characteristics the newborn can confidently be said to have Down syndrome (with less than one in 100.000 false positives).[60] In cases where there are no clinical grounds for making the diagnosis, it has been suggested that parents can reasonably be kept unaware of the initial suspicion.[60] When the diagnosis remains possible, it is recommended to perform karyotype testing and inform the parents.[60]

Management Recommended additional monitoring of children with Down syndrome by DSMIG and CGAAP.[61] Test

Age

Hearing test

6 months, 12 months, then 1/year

T4 and TSH

6 months, then 1/year

Ophthalmic evaluation

6 months, then 1/year

Dental examination

2 years, then every 6 months.

Coeliac disease screening

Between 2 and 3 years of age, or earlier if symptoms occur.

Baseline polysomnography 3 to 4 years, or earlier if symptoms of obstructive sleep apnea occur. Cervical neck x-rays

Between 3 and 5 years of age

Many children with Down syndrome graduate from high school and can do paid work,[] or participate in university education.[] Management strategies such as Early childhood intervention, screening for common problems, medical treatment where indicated, a conducive family environment, and vocational training can improve the overall development of children with Down syndrome. Education and proper care will improve quality of life significantly.[]

Plastic surgery Plastic surgery has sometimes been advocated and performed on children with Down syndrome, based on the assumption that surgery can reduce the facial features associated with Down syndrome, therefore decreasing social stigma, and leading to a better quality of life.[62] Plastic surgery on children with Down syndrome is uncommon,[63] and continues to be controversial. Researchers have found that for facial reconstruction, "... although most patients reported improvements in their child's speech and appearance, independent raters could not readily discern improvement ..."[64] For partial glossectomy (tongue reduction), one researcher found that 1 out of 3 patients "achieved oral competence," with 2 out of 3 showing speech improvement.[65] Len Leshin, physician and author of the ds-health website, has stated, "Despite being in use for over twenty years, there is still not a lot of solid evidence in favor of the use of plastic surgery in children with Down syndrome."[66] The U.S. National Down Syndrome

Down syndrome

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Society has issued a "Position Statement on Cosmetic Surgery for Children with Down Syndrome",[67] which states "The goal of inclusion and acceptance is mutual respect based on who we are as individuals, not how we look."

Cognitive development Individuals with Down syndrome differ considerably in their language and communication skills. It is routine to screen for middle ear problems and hearing loss; low gain hearing aids or other amplification devices can be useful for language learning. Early communication intervention fosters linguistic skills. Language assessments can help profile strengths and weaknesses; for example, it is common for receptive language skills to exceed expressive skills. Individualized speech therapy can target specific speech errors, increase speech intelligibility, and in some cases encourage advanced language and literacy. Augmentative and alternative communication (AAC) methods, such as pointing, body language, objects, or graphics are often used to aid communication. Relatively little research has focused on the effectiveness of communications intervention strategies.[68] Children with Down syndrome may not age emotionally/socially and intellectually at the same rates as children without Down syndrome, so over time the intellectual and emotional gap between children with and without Down syndrome may widen. Complex thinking as required in sciences but also in history, the arts, and other subjects can often be beyond the abilities of some, or achieved much later than in other children. Children with Down syndrome may benefit from mainstreaming (whereby students of differing abilities are placed in classes with their chronological peers) provided that some adjustments are made to the curriculum.[69] Speech delay may require speech therapy to improve expressive language.[19]

Epidemiology The CDC estimates that about 1 of every 691 babies born in the United States each year is born with Down syndrome.[] Each year about 6,000 babies in the United States are born with this condition. Approximately 95% of these are trisomy 21. Maternal age influences the chances of conceiving a baby with Down syndrome. At maternal age 20 to 24, the probability is one in 1562; at age 35 to 39 the probability is one in 214, and above age 45 the probability is one in [] 19. Although the probability increases with maternal age, 80% of children with Down syndrome are born to women under the age of 35,[70] reflecting the overall fertility of that age group. Recent data also suggest that paternal age, especially beyond 42,[71] also increases the risk of Down syndrome manifesting.[72]

Research history

Graph showing probability of Down syndrome as a function of maternal age.

English physician John Langdon Down first characterized Down syndrome as a distinct form of mental disability in 1862, and in a more widely published report in 1866.[73] Due to his perception that children with Down syndrome shared physical facial similarities (epicanthic folds) with those of Blumenbach's Mongolian race, Down used the term mongoloid, derived from prevailing ethnic theory;[] while the term "mongoloid" (also "mongol" or "mongoloid idiot") continued to be used until the early 1970s, it is now considered pejorative and inaccurate and is no longer in common use.[] By the 20th century, Down syndrome had become the most recognizable form of mental disability. Most individuals with Down syndrome were institutionalized, few of the associated medical problems were treated, and most died in infancy or early adult life. With the rise of the eugenics movement, 33 of the (then) 48 U.S. states and several

Down syndrome countries began programs of forced sterilization of individuals with Down syndrome and comparable degrees of disability. "Action T4" in Nazi Germany made public policy of a program of systematic murder.[] Until the middle of the 20th century, the cause of Down syndrome remained unknown. However, the presence in all races, the association with older maternal age, and the rarity of recurrence had been noticed. Standard medical texts assumed it was caused by a combination of inheritable factors that had not been identified. Other theories focused on injuries sustained during birth.[74] With the discovery of karyotype techniques in the 1950s, it became possible to identify abnormalities of chromosomal number or shape. In 1958, Jérôme Lejeune discovered that Down syndrome resulted from an extra chromosome.[75] and, as a result, the condition became known as trisomy 21.[] In 1961, 18 geneticists wrote to the editor of The Lancet suggesting that Mongolian idiocy had "misleading connotations," had become "an embarrassing term," and should be changed.[76] The Lancet supported Down's Syndrome. The World Health Organization (WHO) officially dropped references to mongolism in 1965 after a request by the Mongolian delegate.[] Advocacy groups adapted and parents groups welcomed the elimination of the Mongoloid label that had been a burden to their children. The first parents group in the United States, the Mongoloid Development Council, changed its name to the National Association for Down Syndrome in 1972.[77] In 1975, the United States National Institutes of Health convened a conference to standardize the nomenclature of malformations. They recommended eliminating the possessive form: "The possessive use of an eponym should be discontinued, since the author neither had nor owned the condition."[78] Although both the possessive and non-possessive forms are used in the general population, Down syndrome is the accepted term among professionals in the U.S., Canada and other countries; Down's syndrome is still used in the UK and other areas.[]

Ethical issues Medical ethicist Ronald Green argues that parents have an obligation to avoid 'genetic harm' to their offspring,[79] and Claire Rayner, then a patron of the Down's Syndrome Association, defended testing and abortion saying "The hard facts are that it is costly in terms of human effort, compassion, energy, and finite resources such as money, to care for individuals with handicaps ... People who are not yet parents should ask themselves if they have the right to inflict such burdens on others, however willing they are themselves to take their share of the burden in the beginning."[80] Some physicians and ethicists are concerned about the ethical ramifications of the high abortion rate for this condition.[81] Conservative commentator and father of a son with Down syndrome George Will called it "eugenics by abortion".[82][83] British peer Lord Rix stated that "alas, the birth of a child with Down's syndrome is still considered by many to be an utter tragedy" and that the "ghost of the biologist Sir Francis Galton, who founded the eugenics movement in 1885, still stalks the corridors of many a teaching hospital".[84] Doctor David Mortimer has argued in Ethics & Medicine that "Down's syndrome infants have long been disparaged by some doctors and government bean counters."[85] Some members of the disability rights movement "believe that public support for prenatal diagnosis and abortion based on disability contravenes the movement's basic philosophy and goals."[86] Peter Singer argued that "neither haemophilia nor Down's syndrome is so crippling as to make life not worth living from the inner perspective of the person with the condition. To abort a fetus with one of these disabilities, intending to have another child who will not be disabled, is to treat fetuses as interchangeable or replaceable. If the mother has previously decided to have a certain number of children, say two, then what she is doing, in effect, is rejecting one potential child in favour of another. She could, in defence of her actions, say: the loss of life of the aborted fetus is outweighed by the gain of a better life for the normal child who will be conceived only if the disabled one dies."[87]

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211

Society and culture In most developed countries, since the early 20th century many people with Down syndrome were housed in institutions or colonies and excluded from society. However, since the early 1960s parents and their organizations, educators and other professionals have generally advocated a policy of inclusion,[88] bringing people with any form of mental or physical disability into general society as much as possible. Such organizations included the National Association for Down Syndrome, the first known organization advocating for Down syndrome individuals in the United States founded by Kathryn McGee in 1960;[89] MENCAP advocating for all with mental disabilities, which was founded in the UK in 1946 by Judy Fryd;[90] and the National Down Syndrome Congress, the first truly national organization in the U.S. advocating for Down syndrome families, founded in 1973 by Kathryn McGee and others.[91]

World Down Syndrome Day The first World Down Syndrome Day (WDSD) was held on 21 March 2006. The day and month were chosen to correspond with 21 and trisomy respectively. It was proclaimed by European Down Syndrome Association during their European congress in Palma de Mallorca (February 2005). In the United States, the National Down Syndrome Society observes Down Syndrome Month every October as "a forum for dispelling stereotypes, providing accurate information, and raising awareness of the potential of individuals with Down syndrome."[92] In South Africa, Down Syndrome Awareness Day is held every October 20.[93]

Notable individuals • Chris Burke is an American actor, folk singer, and motivational speaker. He is best known for his character Charles "Corky" Thacher on the television series Life Goes On.

Scottish award-winning film and TV actress Paula Sage receives her BAFTA award with Brian Cox.

• Andrea Friedman: actress who portrayed Corky's girlfriend Amanda in Life Goes On and Ellen in the Family Guy episode "Extra Large Medium".[94] • Stephane Ginnsz, actor (Duo)—In 1996 was first actor with Down syndrome in the lead part of a motion picture.[95] • Sandra Jensen was denied a heart-lung transplant by the Stanford University School of Medicine in California because she had Down syndrome. After pressure from disability rights activists, Stanford University School of Medicine administrators reversed their decision. In 1996, Jensen became the first person with Down syndrome to receive a heart-lung transplant.[96] • Tommy Jessop, British actor who starred with Nicholas Hoult in the BAFTA-nominated BBC drama Coming Down the Mountain.[97] In 2012 he became the first actor with Down Syndrome to play Hamlet professionally, in a production by Blue Apple Theatre.[] • Rene Moreno, subject of "Up Syndrome"—a documentary film about life with Down syndrome.[98][99] • Joey Moss, Edmonton Oilers locker room attendant.[100] • Pablo Pineda, Spanish actor who starred in the semi-autobiographical film Yo También and first student with Down syndrome in Europe to obtain a university degree.[101] • Lauren Potter, American actress, best known for her role as Becky Jackson on the television show Glee. • Isabella Pujols, adopted daughter of Los Angeles Angels first baseman Albert Pujols and inspiration for the Pujols Family Foundation.[102]

Down syndrome • Paula Sage, Scottish film actress and Special Olympics netball athlete.[103] Her role in the 2003 film AfterLife brought her a BAFTA Scotland award for best first time performance and Best Actress in the Bratislava International Film Festival, 2004.[104] • Judith Scott (May 1, 1943 – March 15, 2005) was a highly regarded American outsider sculptor and fiber artist, whose work features in a number of galleries.[105]

Footnotes [1] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=758. 0 [2] http:/ / omim. org/ entry/ 190685 [3] http:/ / www. diseasesdatabase. com/ ddb3898. htm [4] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000997. htm [5] http:/ / www. emedicine. com/ ped/ topic615. htm [6] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D004314 [9] This is similar to 90% results found by [11] Optiz, J.M. (1990). Reflections on the pathogenesis of Down syndrome. In American Journal of Medical Genetics Supplement. 7:38. [12] Richards, M.C. Toward wholeness: Rudolf Steiner education in America. 1980. University Press of New England, N.H. [15] Fuente: Series de porcentajes obtenidas en un amplio estudio realizado por el CMD (Centro Médico Down) de la Fundación Catalana del Síndrome de Down (http:/ / www. fcsd. org/ es/ ), sobre 796 personas con SD. Estudio completo en Josep M. Corretger et al (2005). Síndrome de Down: Aspectos médicos actuales. Ed. Masson, para la Fundación Catalana del Síndrome de Down. ISBN 84-458-1504-0. Pag. 24-32. [18] Borthwick, C. (1996). Racism, IQ and Down's Syndrome. In Disability & Society, Vol 11, No. 3, 1996, pp. 403–410 [19] Also, [24] ACOG Guidelines Bulletin #77 clearly state that the sensitivity of the Quad Test is 81% [34] Weijerman ME, de Winter JP. Clinical practice: The care of children with Down syndrome. European journal of pediatric. 2010;169:1445–1452. [35] Sheehan PZ, Hans PS. UK and Ireland experience of bone anchored hearing aids (BAHA) in individuals with Down Syndrome. International journal of pediatric otorhinolaryngology. 2006; 70, 981-986. [36] Porter H, Tharpe AM. Hearing loss among persons with Down syndrome. Int Rev Res Mental Retardation. 2010; 39, 195-220 [40] See [42] For a description of human karyotype see [43] Mosaic Down syndrome on the Web (http:/ / www. imdsa. org/ ). [44] International Mosaic Down syndrome Association (http:/ / www. imdsa. org/ ). [48] ACOG Guidelines Bulletin #77 state that the sensitivity of the Combined Test is 82-87% [49] NIH FASTER study (NEJM 2005 (353):2001). See also JL Simpson's editorial (NEJM 2005 (353):19). [50] For a current estimate of rates, see [51] ACOG Guidelines Bulletin #77 state that the sensitivity of the Integrated Test is 94–96% [60] (http:/ / fn. bmj. com/ content/ 87/ 3/ F220) [61] Down's syndrome monitoring (http:/ / bestpractice. bmj. com/ best-practice/ monograph/ 700/ follow-up. html) by the BMJ Group. In turn citing: [64] Also, see [65] See also [69] Also, see Finally, see a survey by NDSS on inclusion, [70] Estimate from [72] Warner, Jennifer. "Dad's Age Raises Down Syndrome Risk, Too", [73] For a history of the condition, see or [77] Syndrome (Name Change) from Mongoloid-Charter Document filed by Kay McGee (http:/ / www. scribd. com/ doc/ 11545490/ Down-Syndrome-Name-Change-from-MongoloidCharter-Document-filed-by-Kay-McGeeDown) [78] A planning meeting was held on 20 March 1974, resulting in a letter to The Lancet. The conference was held 10–11 February 1975, and reported to The Lancet shortly afterward. [89] NADS Honors our Founder: Kay McGee (http:/ / www. nads. org/ pages_new/ news/ mcgee_tribute. html) [90] Timeline (http:/ / www. mencap. org. uk/ page. asp?id=1892) [91] History - National Down Syndrome Congress (http:/ / www. ndsccenter. org/ about/ history. php) [92] National Down Syndrome Society (http:/ / www. ndss. org/ index. php?option=com_content& task=view& id=1962& Itemid=233) [93] Down Syndrome South Africa (http:/ / www. downsyndrome. org. za/ main. aspx?artid=54). [94] DSIAM—Down Syndrome in Arts & Media (http:/ / www. dsiam. org/ ) website. Retrieved 02-18-10. [99] from the Corpus-Christi Caller Times

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References Research bibliography • Arron, JR; Winslow, MM; Polleri A (2006). "NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21". Nature 441 (7093): 595–600. doi: 10.1038/nature04678 (http://dx.doi.org/10.1038/ nature04678). PMID  16554754 (http://www.ncbi.nlm.nih.gov/pubmed/16554754). • Epstein CJ (June 2006). "Down's syndrome: critical genes in a critical region". Nature 441 (7093): 582–83. doi: 10.1038/441582a (http://dx.doi.org/10.1038/441582a). PMID  16738647 (http://www.ncbi.nlm.nih.gov/ pubmed/16738647). • Ganong, WJ (2005). Review of Medical Physiology (21st ed.). New York: Mc-Graw Hill. ISBN 0-07-140236-5. • Nelson, DL; Gibbs, RA (2004). "Genetics. The critical region in trisomy 21". Science 306 (5696): 619–21. doi: 10.1126/science.1105226 (http://dx.doi.org/10.1126/science.1105226). PMID  15499000 (http://www.ncbi. nlm.nih.gov/pubmed/15499000). • Olson, LE; Richtsmeier, JT; Leszl, J; Reeves, RH (2004). "A chromosome 21 critical region does not cause specific Down syndrome phenotypes". Science 306 (5696): 687–90. doi: 10.1126/science.1098992 (http://dx. doi.org/10.1126/science.1098992). PMID  15499018 (http://www.ncbi.nlm.nih.gov/pubmed/15499018). • Hattori, M; Fujiyama, A; Taylor, TD (2000). "The DNA sequence of human chromosome 21". Nature 405 (6784): 311–19. doi: 10.1038/35012518 (http://dx.doi.org/10.1038/35012518). PMID  10830953 (http:// www.ncbi.nlm.nih.gov/pubmed/10830953). • Underwood, JCE (2004). General and Systematic Pathology (4th ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07334-1.

General bibliography • Beck, MN (1999). Expecting Adam. New York: Berkley Books. ISBN 0-425-17448-4. • Buckley, S (2000). Living with Down Syndrome (http://books.google.com/?id=__5wB08U2hMC). Portsmouth, UK: The Down Syndrome Educational Trust. ISBN 1-903806-01-1. • Down's Syndrome Research Foundation (2005). Bright Beginnings: A Guide for New Parents (http://www. dsrf-uk.org/PDF/BrightBeginnings_3.pdf). Buckinghamshire, UK: Down's Syndrome Research Foundation. • Dykens EM (2007). "Psychiatric and behavioral disorders in persons with Down syndrome". Ment Retard Dev Disabil Res Rev 13 (3): 272–78. doi: 10.1002/mrdd.20159 (http://dx.doi.org/10.1002/mrdd.20159). PMID  17910080 (http://www.ncbi.nlm.nih.gov/pubmed/17910080). • Hassold, TJ; Patterson, D eds. (1999). Down Syndrome: A Promising Future, Together. New York: Wiley Liss. • Kingsley, J; Levitz M (1994). Count Us In: Growing up with Down Syndrome. San Diego: Harcourt Brace. ISBN 0-15-622660-X. • Koch, Richard; De La Cruz, Felix F, eds. (1975). Downs Syndrome...: Research, Prevention and Management. Proceedings of a Conference on Down's Syndrome. New York: Brunner/Mazel. ISBN 0-87630-093-X • Pueschel, SM; Sustrova, M eds. (1997). Adolescents with Down Syndrome: Toward a More Fulfilling Life. Baltimore, MD: Brookes Paul H • Selikowitz, M (1997). Down Syndrome: The Facts (2nd ed.). Oxford, UK: Oxford University Press. ISBN 0-19-262662-0. • Van Dyke, DC; Mattheis, PJ; Schoon Eberly, S; Williams, J (1995). Medical and Surgical Care for Children with Down Syndrome. Bethesda, MD: Woodbine House. ISBN 0-933149-54-9. • Zuckoff, M (2002). Choosing Naia: A Family's Journey. New York: Beacon Press. ISBN 0-8070-2817-7.

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External links • Facts about Down Syndrome (http://www.nichd.nih.gov/publications/pubs/downsyndrome. cfm#DownSyndrome) from the National Institutes of Health • Tying Your Own Shoes (http://films.nfb.ca/tying-your-own-shoes/) An animated documentary that provides insight into the lives of four adult artists with Down Syndrome, by National Film Board of Canada

214

Edwards syndrome

215

Edwards syndrome Trisomy 18, Edwards Syndrome Classification and external resources

Chromosome 18 [1]

ICD-10

Q91.0

ICD-9

758.2

DiseasesDB

13378

MedlinePlus

001661

eMedicine

ped/652

-Q91.3

[2]

[3] [4] [5] [6]

Edwards syndrome (also known as Trisomy 18 [T18]) is a genetic disorder caused by the presence of all or part of an extra 18th chromosome. This genetic condition almost always results from nondisjunction during meiosis. It is named after John Hilton Edwards, who first described the syndrome in 1960.[7] It is the second most common autosomal trisomy, after Down's syndrome, that carries to term. Edwards syndrome occurs in around one in 6,000 live births and around 80 percent of those affected are female.[48] The majority of fetuses with the syndrome die before birth.[48] The incidence increases as the mother's age increases. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders.

Signs and symptoms Children born with Edwards syndrome may have some or all of the following characteristics: kidney malformations, structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus), intestines protruding outside the body (omphalocele), esophageal atresia, mental retardation, developmental delays, growth deficiency, feeding difficulties, breathing difficulties, and arthrogryposis (a muscle disorder that causes multiple joint contractures at birth).[][] Some physical malformations associated with Edwards syndrome include small head (microcephaly) accompanied by a prominent back portion of the head (occiput); low-set, malformed ears; abnormally small jaw (micrognathia);

Edwards syndrome

216

cleft lip/cleft palate; upturned nose; narrow eyelid folds (palpebral fissures); widely spaced eyes (ocular hypertelorism); drooping of the upper eyelids (ptosis); a short breast bone; clenched hands; choroid plexus cysts; underdeveloped thumbs and or nails, absent radius, webbing of the second and third toes; clubfoot or Rocker bottom feet; and in males, undescended testicles.[][] In utero, the most common characteristic is cardiac anomalies, followed by central nervous system anomalies such as head shape abnormalities. The most common intracranial anomaly is the presence of choroid plexus cysts, which are pockets of fluid on the brain. These are not problematic in themselves, but their presence may be a marker for trisomy 18.[][] Sometimes excess amniotic fluid or polyhydramnios is exhibited.[]

Genetics

Clenched hand and overlapping fingers: index finger overlaps third finger and fifth finger overlaps fourth finger, characteristically seen in Trisomy 18.

Edwards syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on the 18th chromosome, either in whole (trisomy 18) or in part (such as due to translocations). The additional chromosome usually occurs before conception. The effects of the extra copy vary greatly, depending on the extent of the extra copy, genetic history, and chance. Edwards syndrome occurs in all human populations but is more prevalent in female offspring.[] A healthy egg and/or sperm cell contains individual chromosomes, each of which contributes to the 23 pairs of chromosomes needed to form a normal cell with a typical human karyotype of 46 chromosomes. Numerical errors can arise at either of the two meiotic divisions and cause the failure of a chromosome to segregate into the daughter cells (nondisjunction). This results in an extra chromosome, making the haploid number 24 rather than 23. Fertilization of eggs or insemination by sperm that contain an extra chromosome results in trisomy, or three copies of a chromosome rather than two.[8] Trisomy 18 (47,XX,+18) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of chromosome 18; the gamete thus has 24 chromosomes. When combined with a normal gamete from the other parent, the embryo has 47 chromosomes, with three copies of chromosome 18. A small percentage of cases occur when only some of the body's cells have an extra copy of chromosome 18, resulting in a mixed population of cells with a differing number of chromosomes. Such cases are sometimes called mosaic Edwards syndrome. Very rarely, a piece of chromosome 18 becomes attached to another chromosome (translocated) before or after conception. Affected individuals have two copies of chromosome 18 plus extra material from chromosome 18 attached to another chromosome. With a translocation, a person has a partial trisomy for chromosome 18, and the abnormalities are often less severe than for the typical Edwards syndrome.

Prognosis In 2008/2009, there were 495 diagnoses of Edwards syndrome (trisomy 18) in England and Wales, 92% of which were made prenatally. There were 339 abortions, 49 stillbirths/miscarriages/fetal deaths, 72 unknown outcomes, and 35 live births.[9] Because approximately 3% of cases with unknown outcomes are likely to result in a live birth, the total number of live births is estimated to be 37 (2008/09 data are provisional). Major causes of death include apnea and heart abnormalities. It is impossible to predict an exact prognosis during pregnancy or the neonatal period.[] Half of infants with this condition do not survive beyond the first week of life.[10] The median lifespan is 5–15 days.[11][12] About 8% of infants survive longer than 1 year,[13] One percent of children live to age 10, typically in less severe cases of the mosaic Edwards syndrome.[] Parents with surviving children who take part in support groups

Edwards syndrome report that these children enriched their family and their couple irrespective of the length of their lives.[14]

Epidemiology Edwards syndrome occurs in approximately 1 in 6,000 live births, but more conceptions are affected by the syndrome because the majority of those diagnosed with the condition prenatally will not survive the prenatal period.[48][15] Although women in their 20s and early 30s may conceive babies with Edwards syndrome, the risk of conceiving a child with Edwards syndrome increases with a woman's age. The average maternal age for conceiving a child with this disorder is 32½.[16]

References [1] [2] [3] [4] [5] [6] [8]

http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q91. 0 http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q91. 3 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=758. 2 http:/ / www. diseasesdatabase. com/ ddb13378. htm http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001661. htm http:/ / www. emedicine. com/ ped/ topic652. htm For a description of human karyotype see

External links • • • • • • •

Trisomy 18 Foundation, Inc. (http://www.trisomy18.org) SOFT USA Support Organization For Trisomy 18, 13, and Related Disorders (http://www.trisomy.org) Trisomy 18 Support Program (http://www.trisomy18support.org) Chromosome 18 Clinical Research Center (http://www.pediatrics.uthscsa.edu/centers/chromosome18/) SOFT UK Support Organisation for trisomy 13/18 and related disorders (http://www.soft.org.uk) The Chromosome 18 Registry & Research Society (http://www.chromosome18.org) Perinatal Hospice Care - Preparing for birth and death" (http://video.on.nytimes.com/ ?fr_story=79cf26acead199fa0a000074e41deda20072c923) • Humpath #5389 (http://www.humpath.com/spip.php?page=article&id_article=5389)

217

Patau syndrome

218

Patau syndrome Patau syndrome Classification and external resources

Chromosome 13 [1]

ICD-10

Q91.4

ICD-9

758.1

DiseasesDB

13373

MedlinePlus

001660

eMedicine

article/947706

-Q91.7

[2]

[3] [4] [5] [6]

Patau syndrome is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. This can occur either because each cell contains a full extra copy of chromosome 13 (a disorder known as trisomy 13 or trisomy D), or because each cell contains an extra partial copy of the chromosome (i.e., Robertsonian translocation) or because of mosaic Patau syndrome. Full trisomy 13 is caused by nondisjunction of chromosomes during meiosis (the mosaic form is caused by nondisjunction during mitosis). The extra genetic material from chromosome 13 disrupts the normal course of development, causing multiple and complex organ defects. Like all nondisjunction conditions (such as Down syndrome and Edwards syndrome), the risk of this syndrome in the offspring increases with maternal age at pregnancy, with about 31 years being the average.[7] Patau syndrome affects somewhere between 1 in 10,000 and 1 in 21,700 live births.[8]

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219

Causes Patau's syndrome is most often the result of trisomy 13, meaning each cell in the body has three copies of chromosome 13 instead of the usual two. A small percentage of cases occur when only some of the body's cells have an extra copy; such cases are called mosaic Patau. Patau syndrome can also occur when part of chromosome 13 becomes attached to another chromosome (translocated) before or at conception in a Robertsonian translocation. Affected people have two copies of chromosome 13, plus extra material from chromosome 13 attached to another chromosome. With a translocation, the person has a partial trisomy for chromosome 13 and often the physical signs of the syndrome differ from the typical Patau syndrome. Most cases of Patau syndrome are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called non-disjunction can result in reproductive cells with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of the chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 13 in each of the body's cells. Mosaic Patau syndrome is also not inherited. It occurs as a random error during cell division early in fetal development. Patau syndrome due to a translocation can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 13 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 13. Although they do not have signs of Patau syndrome, people who carry this type of balanced translocation are at an increased risk of having children with the condition.

Manifestations and physical findings Of those fetuses that do survive to gestation and subsequent birth, common abnormalities may include: • Nervous system • Mental retardation and motor disorder • Microcephaly • Holoprosencephaly (failure of the forebrain to divide properly). • Structural eye defects, including microphthalmia, Peters anomaly (a type of eye abnormality), cataract, iris and/or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia • Meningomyelocele (a spinal defect) • Musculoskeletal and cutaneous • • • • • • • •

Polydactyly (extra digits) Low-set ears[] Prominent heel Deformed feet known as rocker-bottom feet Omphalocele (abdominal defect) Abnormal palm pattern Overlapping of fingers over thumb Cutis aplasia (missing portion of the skin/hair)

• Cleft palate • Urogenital

A 37 2/7 week gestational age male infant with Patau syndrome demonstrating polydactyly

Patau syndrome • Abnormal genitalia • Kidney defects • Other • Heart defects (ventricular septal defect) • Single umbilical artery[]

Recurrence risk Unless one of the parents is a carrier of a translocation the chances of a couple having another trisomy 13 affected child is less than 1% (less than that of Down syndrome).

History Trisomy 13 was first observed by Thomas Bartholin in 1657,[9] but the chromosomal nature of the disease was ascertained by Dr. Klaus Patau in 1960.[10] The disease is named in his honor. Patau syndrome was also described in Pacific island tribes. These reports were thought to have been caused by radiation from atomic bomb tests. The tribes were temporarily moved before and during the test by an x amount of distance. They were then put back where they had been taken; all of this occurred before it was known how long, or even if, radiation still lingered on after a nuclear explosion.[citation needed] In England and Wales during 2008–09 there were 172 diagnoses of Patau's syndrome (trisomy 13), with 91% of diagnoses made prenatally. There were 111 elective abortions, 14 stillbirth/miscarriage/fetal deaths, 30 outcomes unknown, and 17 live births. Approximately 4% of Patau's syndrome with unknown outcomes are likely to result in a live birth, therefore the total number of live births is estimated to be 18.[11] The small percentage of babies with the full Patau's syndrome who survive birth and early infancy may live to adulthood, and children with mosaic or partial forms of this trisomy may have a completely different and much more hopeful prognosis.[citation needed]

Treatment Medical management of children with Trisomy 13 is planned on a case-by-case basis and depends on the individual circumstances of the patient. Treatment of Patau syndrome focuses on the particular physical problems with which each child is born. Many infants have difficulty surviving the first few days or weeks due to severe neurological problems or complex heart defects. Surgery may be necessary to repair heart defects or cleft lip and cleft palate. Physical, occupational, and speech therapy will help individuals with Patau syndrome reach their full developmental potential. Surviving children are described as happy and parents report that they enrich their lives.[12]

Prognosis More than 80% of children with Patau syndrome die within the first year of life.[13]

References [1] [2] [3] [4] [5] [6]

http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q91. 4 http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q91. 7 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=758. 1 http:/ / www. diseasesdatabase. com/ ddb13373. htm http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001660. htm http:/ / emedicine. medscape. com/ article/ 947706-overview

[8] About.com > Patau Syndrome (Trisomy 13) (http:/ / miscarriage. about. com/ od/ onetimemiscarriages/ p/ patau. htm) From Krissi Danielsson. Updated June 10, 2009 [13] http:/ / www. ncbi. nlm. nih. gov/ pubmedhealth/ PMH0002625/

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Patau syndrome

External links • SOFT USA - Support Organization For Trisomy 18, 13 and Related Disorders (http://www.trisomy.org) • SOFT UK Support Organisation for Trisomy 13/18 and related disorders (http://www.soft.org.uk) • Survivors ~ Living with Trisomy 13 (Patau Syndrome) - An outreach for trisomy and other rare diagnoses (http:// www.livingwithtri13.org) • Trisomy 13 Archived - 300 Carry-to-Term Family Stories Videos (2005-2010) (http://www.trisomy13archive. com) • "Perinatal Hospice Care - Preparing for birth and death" (http://video.on.nytimes.com/ ?fr_story=79cf26acead199fa0a000074e41deda20072c923) at The New York Times • Trisomie 13 Germany (http://www.trisomie13.de), English Translation for Trisomie 13 Germany (http://66. 163.168.225/babelfish/translate_url_content?lp=de_en&url=http://www.trisomie13.de/Kinder/kinder. htm&.intl=us) • Trisomy 13 (http://www.webmd.com/hw/health_guide_atoz/nord218.asp) at WebMD • "Choosing Thomas" (http://www.dallasnews.com/s/dws/photography/2009/thomas/) at Dallas Morning News

221

Cat eye syndrome

222

Cat eye syndrome Cat eye syndrome Classification and external resources OMIM

115470

DiseasesDB

29864

[1]

[2]

Cat Eye Syndrome (CES), or Schmid-Fraccaro syndrome, is a rare condition caused by the short arm (p) and a small section of the long arm (q) of human Chromosome 22 being present three (trisomic) or four times (tetrasomic) instead of the usual two times.[] The term "Cat Eye" syndrome was coined because of the particular appearance of the vertical colobomas in the eyes of some patients. However, over half of the CES patients in the literature do not present with this trait.[citation needed] There is no significant reduction in life expectancy in patients who are not afflicted with one of CES' life threatening abnormalities. An example of the defect after which CES is named.

Genetics The additional chromosome 22 usually arises spontaneously. It may be hereditary and parents may be mosaic for the marker chromosome but show no phenotypic symptoms of the syndrome. The chromosomal area included in the Cat Eye Syndrome "critical region" is 22pter→q11.

History The abnormalities common to cat eye syndrome were first cataloged in 1898.[3] It was described in association with a small marker chromosome in 1965.[4] Early reports of Cat Eye Syndrome discuss the possibility of chromosome 13 involvement. Now, CES is considered to be present with the chromosome 22 trisomy findings.[]

Characteristics • Anal atresia (abnormal obstruction of the anus) • Unilateral or bilateral iris coloboma (absence of tissue from the colored part of the eyes) • Downward-slanting Palpebral fissures (openings between the upper and lower eyelids) • Preauricular pits/tags (small depressions/growths of skin on the outer ears) • Cardiac defects (such as TAPVR) • Kidney problems (missing, extra, or underdeveloped kidneys) • Short stature • Scoliosis/Skeletal problems

Xray image of anal atresia Note that rectum ends blindly and the anus is not present

Cat eye syndrome • Mental retardation -- although most are borderline normal to mildly retarded, and a few even have normal intelligence, CES patients occasionally exhibit moderate to severe retardation. • Micrognathia (smaller jaw) • Hernias • Cleft palate • Rarer malformations can affect almost any organ

References [1] http:/ / omim. org/ entry/ 115470 [2] http:/ / www. diseasesdatabase. com/ ddb29864. htm [3] Haab, O. Albrecht v Graefes. Arch. Ophthal. 24: 257 only, 1879

223

Cri du chat

224

Cri du chat Cri du chat or Cri-du-chat Classification and external resources

Facial features of a patient with Cri du Chat syndrome at age of 8 months (A), 2 years (B), 4 years (C) and 9 years (D) [1]

ICD-10

Q93.4

ICD-9

758.31

OMIM

123450

DiseasesDB

29133

MedlinePlus

001593

eMedicine

ped/504

[2] [3]

[4] [5] [6]

Cri du chat syndrome, also known as chromosome 5p deletion syndrome, 5p minus syndrome or Lejeune’s syndrome, is a rare genetic disorder due to a missing part of chromosome 5. Its name is a French term (cat-cry or call of the cat) referring to the characteristic cat-like cry meow of affected children. It was first described by Jérôme Lejeune in 1963.[7] The condition affects an estimated 1 in 50,000 live births, strikes all ethnicities, and is more common in females by a 4:3 ratio.[] it makes you derp

Signs and symptoms The syndrome gets its name from the characteristic cry of affected infants, which is similar to that of a meowing kitten, due to problems with the larynx and nervous system. About 1/3 of children lose the cry by age 2. Other symptoms of cri du chat syndrome may include: • • • •

feeding problems because of difficulty swallowing and sucking; low birth weight and poor growth; severe cognitive, speech, and motor delays; behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements;

• unusual facial features which may change over time; • excessive drooling;

Cri du chat • • • •

constipation; small head and jaw; wide eyes; skin tags in front of eyes.

Other common findings include hypotonia, microcephaly, growth retardation, a round face with full cheeks, hypertelorism, epicanthal folds, down-slanting palpebral fissures, strabismus, flat nasal bridge, down-turned mouth, micrognathia, low-set ears, short fingers, single palmar creases, and cardiac defects (e.g., ventricular septal defect [VSD], atrial septal defect [ASD], patent ductus arteriosus [PDA], tetralogy of Fallot). People with Cri du chat are fertile and can reproduce. Less frequently encountered findings include cleft lip and palate, preauricular tags and fistulas, thymic dysplasia, intestinal malrotation, megacolon, inguinal hernia, dislocated hips, cryptorchidism, hypospadias, rare renal malformations (e.g., horseshoe kidneys, renal ectopia or agenesis, hydronephrosis), clinodactyly of the fifth fingers, talipes equinovarus, pes planus, syndactyly of the second and third fingers and toes, oligosyndactyly, and hyperextensible joints. The syndrome may also include various dermatoglyphics, including transverse flexion creases, distal axial triradius, increased whorls and arches on digits, and a single palmar crease. Late childhood and adolescence findings include significant intellectual disability, microcephaly, coarsening of facial features, prominent supraorbital ridges, deep-set eyes, hypoplastic nasal bridge, severe malocclusion, and scoliosis. Affected females reach puberty, develop secondary sex characteristics, and menstruate at the usual time. The genital tract is usually normal in females except for a report of a bicornuate uterus. In males, testes are often small, but spermatogenesis is thought to be normal.

Genetics Cri du chat syndrome is due to a partial deletion of the short arm of chromosome number 5, also called "5p monosomy". Approximately 90% of cases result from a sporadic, or randomly occurring, de novo deletion. The remaining 10-15% are due to unequal segregation of a parental balanced translocation where the 5p monosomy is often accompanied by a trisomic portion of the genome. These individuals may have more severe disease than those with isolated monosomy of 5p. Most cases involve total loss of the most distant 20-10% of the material on the short arm. Fewer than 10% of cases have other rare cytogenetic aberrations (e.g., interstitial deletions, mosaicisms, rings and de novo translocations). The deleted chromosome 5 is paternal in origin in about 80% of de novo cases. Loss of a small region in band 5p15.2 (cri du chat critical region) correlates with all the clinical features of the syndrome with the exception of the catlike cry, which maps to band 5p15.3 (catlike critical region). The results suggest that 2 noncontiguous critical regions contain genes involved in this condition's etiology. Two genes in these regions, Semaphorine F (SEMA5A) and delta catenin (CTNND2), are potentially involved in cerebral development. The deletion of the telomerase reverse transcriptase (hTERT) gene localized in 5p15.33 may contribute to the phenotypic changes in cri du chat syndrome as well.

Diagnosis and management Diagnosis is based on the distinctive cry and accompanying physical problems. Genetic counseling and genetic testing may be offered to families with individuals who have cri du chat syndrome. Prenatally the deletion of the Cri du chat related region in the p arm of chromosome 5 can be detected from amniotic fluid or chorionic villi samples with BACs-on-Beads technology.G-banded karyotype of a carrier is also useful.[8] Children may be treated by speech, sound, and occupational therapists. Cardiac abnormalities often require surgical correction.

225

Cri du chat

References [1] [2] [3] [4] [5] [6]

http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q93. 4 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=758. 31 http:/ / omim. org/ entry/ 123450 http:/ / www. diseasesdatabase. com/ ddb29133. htm http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001593. htm http:/ / www. emedicine. com/ ped/ topic504. htm

External links Cri du chat (http:/ / www. dmoz. org/ Health/ Conditions_and_Diseases/ Neurological_Disorders/ Chromosomal/ Cri_du_Chat_Syndrome/) at the Open Directory Project

226

Klinefelter's syndrome

227

Klinefelter's syndrome Klinefelter syndrome Classification and external resources 47,XXY [1]

ICD-10

Q98.0

ICD-9

758.7

MedlinePlus

000382

eMedicine

ped/1252

MeSH

D007713

-Q98.4

[2]

[3] [4] [5] [6]

Klinefelter syndrome or Klinefelter's syndrome, also 47,XXY or XXY syndrome, is a genetic disorder in which there is at least one extra X chromosome to a standard human male karyotype, for a total of 47 chromosomes rather than the 46 found in genetically normal humans.[] While females have an XX chromosomal makeup, and males an XY, individuals with Klinefelter syndrome have at least two X chromosomes and at least one Y chromosome.[] Because of the extra chromosome, individuals with the condition are usually referred to as "XXY males", or "47,XXY males".[] This chromosome constitution (karyotype) exists in roughly between 1:500 to 1:1000 live male births[][7] but many of these people may not show symptoms. If the physical traits associated with the syndrome become apparent, they normally appear after the onset of puberty.[8] In humans, 47,XXY is the most common sex chromosome aneuploidy in males[7] and the second most common condition caused by the presence of extra chromosomes. Other mammals also have the XXY syndrome, including mice.[] Principal effects include hypogonadism and reduced fertility. A variety of other physical and behavioural differences and problems are common, though severity varies and many XXY boys have few detectable symptoms.

Signs and symptoms A person with typical untreated (surgery/hormones) Klinefelter 46,XY/47,XXY mosaic, diagnosed at age 19. Scar from biopsy may be visible on left nipple.

There are many variances within the XXY population, just as within the 46,XY population. While it is possible to characterise XXY males with certain body types and physical characteristics, that in itself should not be the method of identification as to whether or not someone has XXY. The only reliable method of identification is karyotype testing. The degree to which XXY males are affected, both physically and developmentally, differs widely from person to person.

Klinefelter's syndrome

Physical As babies and children, XXY males may have weaker muscles and reduced strength. As they grow older, they tend to become taller than average. They may have less muscle control and coordination than other boys their age.[] During puberty, the physical traits of the syndrome become more evident; because these boys do not produce as much testosterone as other boys, they have a less muscular body, less facial and body hair, and broader hips. As teens, XXY males may have larger breasts, weaker bones, and a lower energy level than other boys.[] By adulthood, XXY males look similar to males without the condition, although they are often taller. In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).[] Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population. About 10% of XXY males have gynecomastia noticeable enough that they may choose to have cosmetic surgery.[] Affected males are often infertile, or may have reduced fertility. Advanced reproductive assistance is sometimes possible.[] The term hypogonadism in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this (primary) hypogonadism, individuals will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.[] Despite this misunderstanding of the term, however, it is true that XXY men may also have microorchidism (i.e., small testicles).[] XXY males are also more likely than other men to have certain health problems, which typically affect females, such as autoimmune disorders, breast cancer, venous thromboembolic disease, and osteoporosis.[][9] In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

Cognitive and developmental Some degree of language learning or reading impairment may be present,[] and neuropsychological testing often reveals deficits in executive functions, although these deficits can often be overcome through early intervention.[10] There may also be delays in motor development which can be addressed through occupational therapy.[11] XXY males may sit up, crawl, and walk later than other infants; they may also struggle in school, both academically and with sports.[]

Cause The extra X chromosome is retained because of a nondisjunction event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in this case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring. The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births.[] Another mechanism for retaining the extra X chromosome is through a nondisjunction event during meiosis II in the female. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. (meiosis) An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring. In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females.[] However, in XXY males, a few genes located in the pseudoautosomal regions of their X chromosomes, have corresponding genes on their Y

228

Klinefelter's syndrome chromosome and are capable of being expressed.[] The first published report of a man with a 47,XXY karyotype was by Patricia Jacobs and John Strong at Western General Hospital in Edinburgh, Scotland in 1959.[] This karyotype was found in a 24-year-old man who had signs of Klinefelter syndrome. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address.[]

Variations 48,XXYY and 48,XXXY occur in 1 in 18,000–50,000 male births. The incidence of 49,XXXXY is 1 in 85,000 to 100,000 male births.[12] These variations are extremely rare. Additional chromosomal material can contribute to cardiac, neurological, orthopedic and other anomalies. Males with Klinefelter syndrome may have a mosaic 47,XXY/46,XY constitutional karyotype and varying degrees of spermatogenic failure. Mosaicism 47,XXY/46,XX with clinical features suggestive of Klinefelter syndrome is very rare. Thus far, only about 10 cases have been described in literature.[] Analogous XXY syndromes are known to occur in cats -- specifically, the presence of calico or tortoiseshell markings in male cats is an indicator of the relevant abnormal karyotype. As such, male cats with calico or tortoiseshell markings are a model organism for Klinefelter syndrome.[13]

Diagnosis About 10% of Klinefelter cases are found by prenatal diagnosis.[14] The first clinical features may appear in early childhood or, more frequently, during puberty, such as lack of secondary sexual characters and aspermatogenesis,[] while tall stature as a symptom can be hard to diagnose during puberty. Despite the presence of small testes, only a quarter of the affected males are recognized as having Klinefelter syndrome at puberty[][] and 25% received their diagnosis in late adulthood: about 64% affected individuals are not recognized as such.[15] Often the diagnosis is made accidentally as a result of examinations and medical visits for reasons not linked to the condition.[] The standard diagnostic method is the analysis of the chromosomes' karyotype on lymphocytes. In the past, the observation of the Barr body was common practice as well.[] To confirm mosaicism, it is also possible to analyze the karyotype using dermal fibroblasts or testicular tissue.[] Other methods may be: research of high serum levels of gonadotropins (follicle-stimulating hormone and luteinizing hormone), presence of azoospermia, determination of the sex chromatin,[] and prenatally via chorionic villus sampling or amniocentesis. A 2002 literature review of elective abortion rates found that approximately 58% of pregnancies in the United States with a diagnosis of Klinefelter syndrome were terminated.[16]

Differential diagnosis The symptoms of Klinefelter syndrome are often variable; therefore, a karyotype analysis should be ordered when small testes, infertility, gynecomastia, long legs/arms, developmental delay, speech/language deficits, learning disabilities/academic issues and/or behavioral issues are present in an individual.[] The differential diagnosis for the Klinefelter syndrome can include the following conditions: fragile X syndrome, Kallman syndrome and Marfan syndrome. The cause of hypogonadism can be attributed to many other different medical conditions. There have been some reports of individuals with Klinefelter syndrome who also have other chromosome abnormalities, such as Down syndrome.[]

229

Klinefelter's syndrome

Treatment The genetic variation is irreversible. Often individuals that have noticeable breast tissue or hypogonadism experience depression and/or social anxiety because they are outside of social norms. This is academically referred to as psychosocial morbidity.[] At least one study indicates that planned and timed support should be provided for young men with Klinefelter syndrome to ameliorate current poor psychosocial outcomes.[] By 2010 over 100 successful pregnancies have been reported using IVF technology with surgically removed sperm material from males with Klinefelter syndrome.[17]

Prognosis Children with a XXY differ little from other children. Although they can face problems during adolescence, often emotional and behavioural, and difficulties at school, most of them can achieve full independence from their families in adulthood. Most can lead a normal, healthy life. The results of a study carried out on 87 Australian adults with the syndrome shows that those who have had a diagnosis and appropriate treatment from a very young age had a significant benefit with respect to those who had been diagnosed in adulthood.[] There is research suggesting Klinefelter syndrome substantially decreases life expectancy among affected individuals, though the evidence is not definitive.[] A 1985 publication identified a greater mortality mainly due to diseases of the aortic valve, development of tumors and possible subarachnoid hemorrhages, reducing life expectancy by about 5 years.[] Later studies have reduced this estimated reduction to an average of 2.1 years.[] These results are still questioned data are not absolute and will need further testing.[]

Epidemiology This syndrome, evenly spread in all ethnic groups, has a prevalence of 1-2 subjects every 1000 males in the general population.[][][][] 3.1 % of infertile males have Klinefelter syndrome. The syndrome is also the main cause of male hypogonadism.[] According to a meta-analysis, the prevalence of the syndrome has increased over the past decades; however, this does not appear to be correlated with the increase of the age of the mother at conception, as no increase was observed in the prevalence of other trisomies of sex chromosomes (XXX and XYY).[]

History The syndrome was named after Harry Klinefelter, who, in 1942, worked with Fuller Albright at Massachusetts General Hospital in Boston, Massachusetts and first described it in the same year.[][] The account given by Klinefelter came to be known as Klinefelter syndrome as his name appeared first on the published paper, and seminiferous tubule dysgenesis was no longer used.

References [1] [2] [3] [4] [5] [6]

http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q98. 0 http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q98. 4 http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=758. 7 http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 000382. htm http:/ / www. emedicine. com/ ped/ topic1252. htm http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D007713

[9] {{Cite journal|last = Hultborn |first = R|last2 = Hanson |first2 = C|last3 = Kopf |first3 = I|last4 = Verbiene |first4 = I|last5 = Warnhammar |first5 = E|last6 = Weimarck |first6 = A |title = Prevalence of Klinefelter syndrome in male breast cancer patients |journal = Anticancer Res.|volume = 17 |issue = 6D |pages = 4293–4297 |date = 1997 November–December |pmid = 9494523|postscript =

230

Klinefelter's syndrome

Further reading • Virginia Isaacs (2012). Living with Klinefelter Syndrome, Trisomy X and 47,XYY: A Guide for Families and Individuals Affected by Extra X and Y Chromosomes. ISBN 978-0-615-57400-4.

External links • Klinefelter syndrome (http://www.dmoz.org/Health/Conditions_and_Diseases/Genetic_Disorders/ Klinefelter_Syndrome//) at the Open Directory Project

231

Androgen insensitivity syndrome

232

Androgen insensitivity syndrome Androgen insensitivity syndrome Classification and external resources

AIS results when the function of the androgen receptor (AR) is impaired. The AR protein (pictured) mediates the effects of androgens in the human body. [1]

ICD-10

E34.5

ICD-9

259.5

OMIM

312300

DiseasesDB

29662

MedlinePlus

001180

eMedicine

ped/2222

MeSH

D013734

GeneReviews

•

[2] [3]

[5]

300068

12975

[4]

[6]

[7] [8] [9]

Androgen Insensitivity Syndrome

[10]

Androgen insensitivity syndrome (AIS) is a condition that results in the partial or complete inability of the cell to respond to androgens.[][][] The unresponsiveness of the cell to the presence of androgenic hormones can impair or prevent the masculinization of male genitalia in the developing fetus, as well as the development of male secondary sexual characteristics at puberty, but does not significantly impair female genital or sexual development.[][] As such, the insensitivity to androgens is Women with AIS and related DSD conditions clinically significant only when it occurs in genetic males (i.e. individuals with a Y-chromosome, or more specifically, an SRY gene).[] Clinical phenotypes in these individuals range from a normal male habitus with mild spermatogenic defect or reduced secondary terminal hair, to a full female habitus, despite the presence of a Y-chromosome.[][][][][][] AIS is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia are that of a normal female; mild

Androgen insensitivity syndrome

233

androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are that of a normal male, and partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized.[][][][][][][][][] Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.[]

Signs and symptoms AIS is broken down into three classes based on phenotype: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS).[][][][][][][][][] A supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995.[] The first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization; grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of decreasingly masculinized genitalia that lie in the interim.[] Grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondary terminal hair; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent.[] The Quigley scale can be used in conjunction with the traditional three classes of AIS to provide additional information regarding the degree of genital masculinization, and is particularly useful when the diagnosis is PAIS.[][]

Genetics The human androgen receptor (AR) is a protein encoded by a gene located on the proximal long arm of the X chromosome (locus Xq11-Xq12).[] The protein coding region consists of approximately 2,757 nucleotides (919 codons) spanning eight exons, designated 1-8 or A-H.[][] Introns vary in size between 0.7 and 26 kb.[] Like other nuclear receptors, the androgen receptor protein consists of several functional domains: the transactivation domain (also called the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain, the hinge region, and the steroid-binding domain (also called the carboxyl-terminal ligand-binding domain).[][][][] The transactivation domain is encoded by exon 1, and makes up more than half of the AR protein.[] Exons 2 and 3 encode the DNA-binding domain, while the 5' portion of exon 4 encodes the hinge region.[] The remainder of exon 4 through exon 8 encodes the ligand binding domain.[]

Location and structure of the human androgen receptor. Top, The AR gene is located on the proximal long arm of the X chromosome. Middle, The eight exons are separated by introns of various lengths. Bottom, Illustration of the AR protein, with primary functional domains labeled (not representative of actual 3-D [] structure).

Trinucleotide satellite lengths and AR transcriptional activity The androgen receptor gene contains two polymorphic trinucleotide microsatellites in exon 1.[] The first microsatellite (nearest the 5' end) contains 8 [] to 60 [][] repetitions of the glutamine codon "CAG" and is thus known as the polyglutamine tract.[] The second microsatellite contains 4 [] to 31 [] repetitions of the glycine codon "GGC" and is known as the polyglycine tract.[] The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18.[] In men, disease states are associated with extremes in polyglutamine tract length; prostate cancer,[] hepatocellular carcinoma,[] and mental retardation [] are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more.[] Some studies indicate that the length of the polyglutamine tract is inversely correlated with

Androgen insensitivity syndrome transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility [][][] and undermasculinized genitalia in men.[] However, other studies have indicated that no such correlation exists.[][][][][][] A comprehensive meta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded that these discrepancies could be resolved when sample size and study design are taken into account.[] Some studies suggest that longer polyglycine tract lengths are also associated with genital masculinization defects in men.[][] Other studies find no such association.[]

AR mutations As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow.[] Inheritance is typically maternal and follows an X-linked recessive pattern;[][] individuals with a 46,XY karyotype will always express the mutant gene since they only have one X chromosome, whereas 46,XX carriers will be minimally affected. 30% of the time, the AR mutation is a spontaneous result, and is not inherited.[] Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself.[] In one study,[] it was found that 3 out of 8 de novo mutations occurred in the post-zygotic stage, leading to the estimate that up to one third of de novo mutations result in somatic mosaicism.[] It is worthwhile to note that not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14 percent of genetic males,[][][][] and is thought to adversely affect only a small number of individuals when other genetic factors are present.[]

Other causes Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation,[] as well as between 27% [][] and 72% [] of individuals with PAIS. In one patient, it was shown that the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1) protein.[] In another patient, it was shown that CAIS was the result of a deficit in the transmission of a transactivating signal from the N-terminal region of the normal androgen receptor to the basal transcription machinery of the cell.[] It was suggested that a coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor was deficient in this patient.[] The signal disruption could not be corrected by supplementation with any coactivators known at the time, nor was the absent coactivator protein characterized, which left some in the field unconvinced that a mutant coactivator would explain the mechanism of androgen resistance in CAIS or PAIS patients with a normal AR gene.[]

XY karyotype Depending on the mutation, a person with a (46,XY karyotype) and AIS can have either a male (MAIS) or female (CAIS) phenotype,[] or may have genitalia that is only partially masculinized (PAIS).[] The gonads are testes regardless of phenotype due to the influence of the Y-chromosome.[][] A 46,XY female thus does not have ovaries or a uterus,[] and can neither contribute an egg towards conception nor gestate a child. Several case studies of fertile 46,XY males with androgen insensitivity have been published,[][][][][] although this group is thought to be a minority.[] Additionally, some infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone.[][] A genetic male conceived by a man with androgen insensitivity would not receive his father's X chromosome, and thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, and would thus become a carrier.

234

Androgen insensitivity syndrome

XX karyotype Genetic females (46,XX karyotype) have two X chromosomes, and thus have two AR genes. A mutation in one (but not both) of the AR genes results in a minimally affected, fertile, female carrier. Some carriers have been noted to have slightly reduced body hair, delayed puberty, and / or tall stature, presumably due to skewed X-inactivation.[][] A female carrier will pass the affected AR gene to her children 50% of the time. If the affected child is a genetic female, she too will be a carrier. An affected 46,XY child will have androgen insensitivity syndrome. A genetic female with mutations in both AR genes could theoretically result from the union of a fertile man with androgen insensitivity and a female carrier of the gene, or from de novo mutation. However, given the scarcity of fertile androgen insensitive men and low incidence of AR mutation, the chances of this occurrence is small. The phenotype of such an individual is a matter of speculation; as of 2010, no such documented case has been published.

Correlation of genotype and phenotype Individuals with partial androgen insensitivity, unlike those with the complete or mild forms, present at birth with ambiguous genitalia, and the decision to raise the child as male or female is often not obvious.[][][] Unfortunately, it is often the case that little information regarding phenotype can be gleaned from precise knowledge of the AR mutation itself; it is well established that the same AR mutation may cause significant variation in the degree of masculinization in different individuals, even among members of the same family.[][][][][][][][][][] Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the polyglutamine and polyglycine tracts,[] sensitivity to and variations in the intrauterine endocrine milieu,[] the effect of coregulatory proteins that are active in Sertoli cells,[][] somatic mosaicism,[] expression of the 5RD2 gene in genital skin fibroblasts,[] reduced AR transcription and translation from factors other than mutations in the AR coding region,[] an unidentified coactivator protein,[] enzyme deficiencies such as 21-hydroxylase deficiency,[] or other genetic variations such as a mutant steroidogenic factor-1 (SF-1) protein.[] The degree of variation, however, does not appear to be constant across all AR mutations, and is much more extreme in some.[][][][] Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity.[]

235

Androgen insensitivity syndrome

236

Pathophysiology Androgens and the androgen receptor The effects that androgens have on the human body --- virilization, masculinization, anabolism, etc. --- are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptors; the androgen receptor mediates the effects of androgens in the human body.[] Likewise, under normal circumstances, the androgen receptor itself is inactive in the cell until androgen binding occurs.[] The following series of steps illustrates how androgens and the androgen receptor work together to produce androgenic effects:[][][][][][][] 1. Androgen enters the cell. a. Only certain organs in the body, such as the gonads and the adrenal glands, produce the androgen testosterone. b. Testosterone is converted into dihydrotestosterone, a chemically similar androgen, in cells containing the 5 alpha reductase enzyme. c. Both androgens exert their influence through binding with the androgen receptor. 3. Androgen binds with the androgen receptor.

Normal function of the androgen receptor. Testosterone (T) enters the cell and, if 5-alpha-reductase is present, is converted into dihydrotestone (DHT). Upon steroid binding, the androgen receptor (AR) undergoes a conformational change and releases heat shock proteins (hsps). Phosphorylation (P) occurs before or after steroid binding. The AR translocates to the nucleus where dimerization, DNA binding, and the recruitment of coactivators occur. Target genes are transcribed (mRNA) and [][][][] translated into proteins.

a. The androgen receptor is expressed ubiquitously throughout the tissues of the human body. b. Before it binds with an androgen, the androgen receptor is bound to heat shock proteins. c. These heat shock proteins are released upon androgen binding. d. Androgen binding induces a stabilizing, conformational change in the androgen receptor. e. The two zinc fingers of the DNA-binding domain are exposed as a result of this new conformation. f. AR stability is thought to be aided by type II coregulators, which modulate protein folding and androgen binding, or facilitate NH2/carboxyl-terminal interaction. 5. The hormone-activated androgen receptor is phosphorylated. a. Receptor phosphorylation can occur before androgen binding, although the presence of androgen promotes hyperphosphorylation. b. The biological ramifications of receptor phosphorylation are unknown. 6. The hormone-activated androgen receptor translocates to the nucleus. a. Nucleocytoplasmic transport is in part facilitated by an amino acid sequence on the AR called the nuclear localization signal. b. The AR's nuclear localization signal is primarily encoded in the hinge region of the AR gene. 7. Homodimerization occurs. a. Dimerization is mediated by the second (nearest the 3' end) zinc finger. 8. DNA binding to regulatory androgen response elements occurs. a. Target genes contain (or are flanked by) transcriptional enhancer nucleotide sequences that interact with the first zinc finger. b. These areas are called androgen response elements. 9. Coactivators are recruited by the AR.

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a. Type I coactivators (i.e., coregulators) are thought to influence AR transcriptional activity by facilitating DNA occupancy, chromatin remodeling, or the recruitment of general transcription factors associated with RNA polymerase II holocomplex. 10. Target gene transcription ensues. In this way, androgens bound to androgen receptors regulate the expression of target genes, and thus produce androgenic effects. It is theoretically possible for certain mutant androgen receptors to function without androgens; in vitro studies have demonstrated that a mutant androgen receptor protein can induce transcription in the absence of androgen if its steroid binding domain is deleted.[][] Conversely, the steroid-binding domain may act to repress the AR transactivation domain, perhaps due to the AR's unliganded conformation.[]

Androgens in fetal development Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for Barr bodies or a Y-chromosome.[] The gonads begin as bulges of tissue called the genital ridges at the back of the abdominal cavity, near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla, and are called indifferent gonads.[] By the sixth week, the indifferent gonads begin to differentiate according to genetic sex. If the karyotype is 46,XY, testes develop due to the influence of the Y chromosome’s SRY gene.[][] This process does not require the presence of androgen, nor a functional androgen receptor.[][]

Sexual differentiation. The human embryo has indifferent sex accessory ducts until the seventh [] week of development.

Until approximately the seventh week of development, the embryo has indifferent sex accessory ducts, which consist of two pairs of ducts: the Müllerian ducts and the Wolffian ducts.[] The testes secrete anti-Müllerian hormone around this time to suppress the development of the Müllerian ducts, and cause their degeneration.[] Without this anti-Müllerian hormone, the Müllerian ducts develop into the female internal genitalia (uterus, cervix, fallopian tubes, and upper vaginal barrel).[] Unlike the Müllerian ducts, the Wolffian ducts will not continue to develop by default.[] In the presence of testosterone and functional androgen receptors, the Wolffian ducts develop into the epididymides, vasa deferentia, and seminal vesicles.[] If the testes fail to secrete testosterone, or the androgen receptors do not function properly, the Wolffian ducts degenerate.[]

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Masculinization of the external genitalia (the penis, penile urethra, and scrotum), as well as the prostate, are dependent on the androgen dihydrotestosterone.[][][][] Testosterone is converted into [] dihydrotestosterone by the 5-alpha reductase enzyme. If this enzyme is absent or deficient, then dihydrotestosterone will not be created, and the external male genitalia will not develop properly.[][][][][] As is the case with the internal male genitalia, a functional androgen receptor is needed in order for dihydrotestosterone to regulate the transcription of target genes involved in development.[]

Pathogenesis of Androgen Insensitivity Syndrome

Masculinization of the male genitalia is dependent on both testosterone and [] dihydrotestosterone.

Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex.[] AIS can result if even one of these steps is significantly disrupted, as each step is required in order for androgens to successfully activate the AR and regulate gene expression.[] Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides. This predictive ability is primarily retrospective in origin; the different functional domains of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR.[] For example, mutations in the steroid binding domain have been known to affect androgen binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the DNA-binding domain have been known to affect dimerization and binding to target DNA, and mutations in the transactivation domain have been known to affect target gene transcription regulation.[][] Unfortunately, even when the affected functional domain is known, it is difficult to predict the phenotypical consequences of a particular mutation (see Correlation of genotype and phenotype). Some mutations can adversely impact more than one functional domain. For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact.[] A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein.[] The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.[] Other, more complex relationships have been observed as a consequence of mutated AR; some mutations associated with male phenotypes have been linked to male breast cancer, prostate cancer, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system.[][][][][] The form of breast cancer that is seen in some men with partial androgen insensitivity syndrome is caused by a mutation in the AR's DNA-binding domain.[][] It has been hypothesized that this mutation causes a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the estrogen receptor protein, to cause cancerous growth.[] The etiology of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in pathology. The trinucleotide repeat expansion of the polyglutamine tract of the AR gene that is associated with SBMA results in the synthesis of a misfolded AR protein that the cell fails to properly proteolyze and disperse.[] These misfolded AR proteins form aggregates in the cell cytoplasm and nucleus.[] Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the neurodegenerative symptoms associated with SBMA.[]

Androgen insensitivity syndrome

Diagnosis The phenotypes that result from the insensitivity to androgens are not unique to AIS, and thus the diagnosis of AIS requires thorough exclusion of other causes.[][] Clinical findings indicative of AIS include the presence of a short vagina [] or undermasculinized genitalia,[][][] partial or complete regression of Müllerian structures,[11] bilateral nondysplastic testes,[] and impaired spermatogenesis and / or virilization.[][][][] Laboratory findings include a 46,XY karyotype [] and normal or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels.[][] The androgen binding activity of genital skin fibroblasts is typically diminished,[][] although exceptions have been reported.[] Conversion of testosterone to dihydrotestosterone may be impaired.[] The diagnosis of AIS is confirmed if androgen receptor gene sequencing reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an AR mutation (see Other Causes).[][][][] Each of the three types of AIS --- complete, partial, and mild --- has a different list of differential diagnoses to consider.[] Depending on the form of AIS that is suspected, the list of differentials can include:[][][][][] 1. Chromosomal anomalies: 1. Klinefelter syndrome (47,XXY karyotype) 2. Turner syndrome (45,XO karyotype) 3. Mixed gonadal dysgenesis (45,XO/46,XY karyotype) 4. Tetragametic chimerism (46,XX/46,XY karyotype) 3. Androgen biosynthetic dysfunction in 46,XY individuals: 1. Luteinizing hormone (LH) receptor mutations 2. Smith-Lemli-Opitz syndrome (associated with mental retardation) 3. Lipoid congenital adrenal hyperplasia 4. 3β-hydroxysteroid dehydrogenase 2 deficiency 5. 17α-hydroxylase deficiency 6. 17,20 lyase deficiency 7. 17β-hydroxysteroid dehydrogenase deficiency 8. 5α-reductase deficiency 5. Androgen excess in 46,XX individuals: 1. 21-hydroxylase deficiency 2. 3β-hydroxysteroid dehydrogenase 2 deficiency 3. Cytochrome P450 oxidoreductase deficiency (disorder in mother causes 46,XX fetal virilization) 4. 11β-hydroxylase deficiency 5. Aromatase deficiency 6. Glucocorticoid receptor mutations 7. Maternal virilizing tumor (e.g. luteoma) 8. Increased androgen exposure in utero, not otherwise specified (e.g. androgenic drugs) 7. Developmental 1. 2. 3. 4. 5. 6. 7.

Mayer-Rokitansky-Küster-Hauser syndrome (46,XX karyotype) Swyer syndrome (46,XY karyotype) XX gonadal dysgenesis (46,XX karyotype) Leydig cell agenesis or hypoplasia, not otherwise specified (46,XY karyotype) Absent (vanishing) testes syndrome Ovotesticular DSD Testicular DSD (i.e. 46,XX sex reversal)

9. Teratogenic causes (e.g. estrogens, antiestrogens) 10. Other causes:

239

Androgen insensitivity syndrome 1. Frasier syndrome (associated with progressive glomerulopathy) 2. Denys-Drash syndrome (associated with nephropathy and Wilms tumor) 3. WAGR syndrome (associated with Wilms tumor and aniridia) 4. McKusick-Kaufman syndrome (associated with postaxial polydactyly) 5. Robinow syndrome (associated with dwarfism) 6. Aarskog-Scott syndrome (associated with facial anomalies) 7. Hand-foot-genital syndrome (associated with limb malformations) 8. Popliteal pterygium syndrome (associated with extensive webbing behind knees) 9. Kallmann syndrome (often associated with anosmia) 10. Hypospadias not otherwise specified 11. Cryptorchidism not otherwise specified 12. vaginal atresia not otherwise specified

Management Management of AIS is currently limited to symptomatic management; methods to correct a malfunctioning androgen receptor protein that result from an AR gene mutation are not currently available. Areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, and genetic and psychological counseling.

Epidemiology Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small population size, and thus are known to be imprecise.[] CAIS is estimated to occur in 1 out of every 20,400 46,XY births.[] A nationwide survey in The Netherlands based on patients with genetic confirmation of the diagnosis estimates that the minimal incidence of CAIS is 1 in 99,000.[] The incidence of PAIS is estimated to be 1 in 130,000.[] Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility,[] and thus its true prevalence is unknown.[]

History Recorded descriptions of the effects of androgen insensitivity syndrome date back for hundreds of years, although significant understanding of its underlying histopathology would not occur until the 1950s.[] The taxonomy and nomenclature associated with androgen insensitivity went through a significant evolution that paralleled this understanding.

Timeline of major milestones 1. 1950: Lawson Wilkins administers daily methyltestosterone to a 46,XY female patient, who shows no signs of virilization. His experiment is the first documented demonstration of the pathophysiology of androgen insensitivity syndrome.[][12] 2. 1970: Mary F. Lyon and Susan Hawkes report that a gene on the X chromosome caused complete insensitivity to androgens in mice.[][] 3. 1981: Barbara Migeon et al. narrow down the locus of the human androgen receptor gene (or a factor controlling the androgen receptor gene) to somewhere between Xq11 and Xq13.[][] 4. 1988: The human androgen receptor gene is first cloned and partially analyzed by multiple parties.[][] Terry Brown et al. report the first mutations proven to cause AIS.[][] 5. 1989: Terry Brown et al. report the exact locus of the AR gene (Xq11-Xq12),[] and Dennis Lubahn et al. publishes its intron-exon boundaries.[]

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Androgen insensitivity syndrome 6. 1994: The androgen receptor gene mutations database is created to provide a comprehensive listing of mutations published in journals and conference proceedings.[]

Early terminology The first descriptions of the effects of androgen insensitivity appeared in the medical literature as individual case reports or as part of a comprehensive description of intersex physicalities. In 1839, Scottish obstetrician Sir James Young Simpson published one such description [13] in an exhaustive study of intersexuality that has been credited with advancing the medical community's understanding of the subject.[] Simpson's system of taxonomy, however, was far from the first; taxonomies / descriptions for the classification of intersexuality were developed by Italian physician and physicist Fortuné Affaitati in 1549,[14][15] French surgeon Ambroise Paré in 1573,[][16] French physician and sexology pioneer Nicolas Venette in 1687 (under the pseudonym Vénitien Salocini),[17][18] and French Zoologist Isidore Geoffroy St. Hilaire in 1832.[19] All five of the aforementioned authors used the colloquial term "hermaphrodite" as the foundation of their taxonomies, although Simpson himself questioned the propriety of the word in his publication.[13] Use of the word "hermaphrodite" in the medical literature has persisted to this day,[][] although its propriety is still in question. An alternative system of nomenclature has been recently suggested,[] but the subject of exactly which word or words should be used in its place still one of much debate.[][][][][]

Pseudohermaphroditism "Pseudohermaphroditism" has, until very recently,[] been the term used in the medical literature to describe the condition of an individual whose gonads and karyotype do not match the external genitalia in the "Pudenda pseudo-hermaphroditi ovini." Illustration of ambiguous genitalia from Frederik gender binary sense. For example, 46,XY individuals who have a Ruysch’s Thesaurus Anitomicus Octavius, female phenotype, but also have testes instead of ovaries --- a group [20] 1709. that includes all individuals with complete androgen insensitivity (CAIS), as well as some individuals with partial androgen insensitivity (PAIS) --- are classified as having "male pseudohermaphroditism," while individuals with both an ovary and a testis (or at least one ovotestis) are classified as having "true hermaphroditism.".[][] Usage of the word in the medical literature predates the discovery of the chromosome, and thus its definition has not always taken karyotype into account when determining an individual's sex. Previous definitions of "pseudohermaphroditism" relied on perceived inconsistencies between the internal and external organs; the "true" sex of an individual was determined by the internal organs, and the external organs determined the "perceived" sex of an individual.[13][19] German-Swiss pathologist Edwin Klebs is sometimes noted for using the word "pseudohermaphroditism" in his taxonomy of intersexuality in 1876,[21] although the word is clearly not his invention as is sometimes reported; the history of the word "pseudohermaphrodite," and the corresponding desire to separate "true" hermaphrodites from "false," "spurious," or "pseudo" hermaphrodites, dates back to at least 1709, when Dutch anatomist Frederik Ruysch used it in a publication describing a subject with testes and a mostly female phenotype.[20] "Pseudohermaphrodite" also appeared in the Acta Eruditorum later that same year, in a review of Ruysch's work.[22] There is also evidence that the word was already being used by the German and French medical community long before Klebs used it; German physiologist Johannes Peter Müller equated "pseudohermaphroditism" with a sub-class of hermaphroditism from St. Hilaire's taxonomy in a publication dated 1834,[23] and by the 1840s "pseudo-hermaphroditism" was appearing in several French and German publications, including dictionaries.[24][25][26][27]

241

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Testicular feminization In 1953, American gynecologist John Morris provided the first full description of what he called "testicular feminization syndrome" based on 82 cases compiled from the medical literature, including 2 of his own patients.[][][] The term "testicular feminization" was coined to reflect Morris' observation that the testicles in these patients produced a hormone that had a feminizing effect on the body, a phenomenon that is now understood to be due to the inaction of androgens, and subsequent aromatization of testosterone into estrogen.[] A few years before Morris published his landmark paper, Lawson Wilkins had shown through his own experiments that unresponsiveness of the target cell to the action of androgenic hormones was a cause of "male pseudohermaphroditism".[][12] Wilkins' work, which clearly demonstrated the lack of a therapeutic effect when 46,XY women were treated with androgens, caused a gradual shift in nomenclature from "testicular feminization" to "androgen resistance".[]

Other names A distinct name has been given to many of the various presentations of androgen insensitivity syndrome, such as Reifenstein syndrome (1947),[] Goldberg-Maxwell syndrome (1948),[] Morris' syndrome (1953),[] Gilbert-Dreyfus syndrome (1957),[] Lub's syndrome (1959),[] "incomplete testicular feminization" (1963),[] Rosewater syndrome (1965),[] and Aiman's syndrome (1979).[] Since it was not understood that these different presentations were all caused by the same set of mutations in the androgen receptor gene, a unique name was given to each new combination of symptoms, resulting in a complicated stratification of seemingly disparate disorders.[][] Over the last 60 years, as reports of strikingly different phenotypes were reported to occur even among members of the same family, and as steady progress was made towards the understanding of the underlying molecular pathogenesis of AIS, it has been demonstrated that these disorders are different phenotypic expressions of one syndrome caused by molecular defects in the androgen receptor gene.[][][][] Androgen insensitivity syndrome (AIS) is now the accepted terminology for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones.[] AIS is broken down into three classes based on phenotype: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS).[][][][][][][][][] CAIS encompasses the phenotypes previously described by "testicular feminization," Morris' syndrome, and Goldberg-Maxwell syndrome;[][] PAIS includes Reifenstein syndrome, Gilbert-Dreyfus syndrome, Lub's syndrome, "incomplete testicular feminization," and Rosewater syndrome;[][][] and MAIS includes Aiman's syndrome.[] The more virilized phenotypes of AIS have sometimes been described as "undervirilized male syndrome," "infertile male syndrome," "undervirilized fertile male syndrome," etc., before evidence was reported that these conditions were caused by mutations in the androgen receptor gene.[] These diagnoses were used to describe a variety of mild defects in virilization; as a result, the phenotypes of some men that have been diagnosed as such are better described by PAIS (e.g. micropenis, hypospadias and undescended testes), while others are better described by MAIS (e.g. isolated infertility or gynecomastia).[][][][][][]

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Popular culture The 1991 novel Ring (later adopted into English "The Ring" series) describes that the central antagonist Sadako as having this syndrome. In Season 2 Episode 13 "Skin Deep" of House, the main patient's testicular cancer is mistaken for an ovary due to the patient's undiscovered AIS.

References [1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E34. 5 [2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=259. 5 [3] http:/ / omim. org/ entry/ 312300 [4] http:/ / omim. org/ entry/ 300068 [5] http:/ / www. diseasesdatabase. com/ ddb29662. htm [6] http:/ / www. diseasesdatabase. com/ ddb12975. htm [7] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001180. htm [8] http:/ / www. emedicine. com/ ped/ topic2222. htm [9] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D013734 [10] http:/ / www. ncbi. nlm. nih. gov/ books/ NBK1429/ [11] Nichols JL, Bieber EJ, Gell JS. Case of sisters with complete androgen insensitivity syndrome and discordant Müllerian remnants. Fertil Steril. 2009;91:932e15-e18. [12] Wilkins L. Heterosexual development. In: The diagnosis and treatment of endocrine disorders in childhood and adolescence. Springfield, IL: Charles C Thomas, 1950, pp. 256-279. [13] Simpson JY. Hermaphroditism. In: Todd RB, ed. Cyclopaedia of Anatomy and Physiology, Vol II. London: Longman, Brown, Green, Longmans, & Roberts 1839;2:684-738. [14] Affaitati F [Affaitat]. De hermaphroditis. Venet. 1549. [15] Panckoucke CLF, ed. Dictionnaire des sciences médicales - biographie médicale, 1st ed. Paris: Panckoucke 1820;1:59. [16] Paré, A. Des monstres et prodiges. Paris: Dupuys 1573. [17] Venette N [Vénitien Salocini]. Tableau de l'amour humain considéré dans l'état du mariage. A Parme: Chez Franc d'Amour 1687. [18] Jacob G. Tractatus de hermaphroditis. London: E. Curll 1718. [19] Saint Hilaire IG. Histoire générale et particulière des anomalies de l'organisation. Paris: J.-B. Baillière 1832-1836. [20] Ruysch F. Thesaurus anatomicus octavus. Amsterdam: Joannem Wolters 1709. p. 33, Plate II. [21] Klebs E. Handbuch der pathologischen anatomie. Berlin: A. Hirschwald 1876;1:718. [22] Mencke JB, ed. Acta eruditorum anno mdccix. Leipzig: Joh. Grossii Haeredes, Joh. Frid. Gleditsch, & Frid. Groschuf. 1709;28:272-274. [23] Müller JP, ed. Archiv für Anatomie, Physiologie und wissenschaftliche Medicin. Berlin: G. Eichler 1834, p. 171. [24] Académie française. Complément du Dictionnaire de l'Académie française. Paris: Chez Firmin Didot Fréres 1843, p. 997. [25] Ritter von Raiman JN, Edlen von Rosas A, Fischer SC, Wisgrill J, eds. Medicinische Jahrbücher des kaiserlich-königlichen österreichischen Staates (volume 22). Vienna: Carl Gerold 1840;22:380-384. [26] Bertuch FJ, Schütz CG, eds. Allgemeine Literatur-Zeitung Issues 1-97. Leipzig 1815, pp. 257-260. [27] Peschier A, Mozin DJ, eds. Supplément au dictionnaire complet des langues française et allemande de l'abbe Mozin. Paris: Stuttgart et Augsbourg 1859, p. 333.

External links Information • Androgen Insensitivity Syndrome (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene& part=androgen) at NIH/UW GeneTests • Online 'Mendelian Inheritance in Man' (OMIM) Androgen Insensitivity Syndrome -300068 (http://omim.org/ entry/300068), 313700 (http://omim.org/entry/313700) • An Australian parent/patient booklet on CAIS (http://www.rch.org.au/publications/CAIS.html) • The Secret of My Sex (http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/ the-secret-of-my-sex-411032.html) news article • Women With Male DNA All Female (http://abcnews.go.com/Health/MedicalMysteries/Story?id=5465752& page=1) news article at ABCnews.com

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Patient groups • • • •

AIS Support Group AISSG (UK and International) (http://www.aissg.org) AIS-DSD Support Group for Women & Families (http://www.aisdsd.org) AIS Support Group (Australasia) (http://www.vicnet.net.au/~aissg) Intersex Support Forums (US and International) (http://www.bodieslikeours.com/forums/)

244

XX male syndrome

245

XX male syndrome XX male syndrome Classification and external resources ICD-10

(Q98.3

OMIM

278850

[1]

)

[2]

XX male syndrome (also called de la Chapelle syndrome, for a researcher who characterized it in 1972[3]) is a rare sex chromosomal disorder. Usually it is caused by unequal crossing over between X and Y chromosomes during meiosis in the father, which results in the X chromosome containing the normally-male SRY gene. When this X combines with a normal X from the mother during fertilization, the result is an XX male. This syndrome occurs in approximately four or five in 100,000 individuals, making it less common than Klinefelter syndrome.[][4]

Presentation Symptoms usually include small testes and subjects are invariably sterile. Individuals with this condition sometimes have feminine characteristics, with varying degrees of gynecomastia but with no intra-abdominal Müllerian tissue.[] According to research at the University of Oklahoma health science centers, most XX males are not stereotypically feminine and are typical boys and men[citation needed] although other reports suggest that facial hair growth is usually poor and libido is diminished, with notable exceptions.[][5]

Clinical diagnosis • • • •

Standard XX karyotype in two tissues (with at least one, or both, containing the male SRY gene) Male external genitalia, sometimes showing hypospadias Two testes which may or may not have descended the inguinal canal. Most XX males have descended testes. Absence of Müllerian tissue

Pathophysiology Males typically have one X chromosome and one Y chromosome in each diploid cell of their bodies. Females typically have two X chromosomes. XX males have two X chromosomes, with one of them containing genetic material from the Y chromosome, making them phenotypically male; they are genetically female but otherwise appear to be male.

XX male syndrome

External links • GeneReviews/NCBI/NIH/UW entry on 46,XX Testicular Disorder of Sex Development [6] • GeneReviews/NCBI/NIH/UW entry on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis [7]

References [1] [2] [4] [6] [7]

http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q98. 3 http:/ / omim. org/ entry/ 278850 http:/ / www. healthline. com/ galecontent/ xx-male-syndrome Healthline.com: XX Male Syndrome http:/ / www. ncbi. nlm. nih. gov/ books/ NBK1416/ http:/ / www. ncbi. nlm. nih. gov/ books/ NBK1547/

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XY gonadal dysgenesis

247

XY gonadal dysgenesis Swyer syndrome Classification and external resources [1]

ICD-10

Q56.4

ICD-9

752.7

OMIM

400044

DiseasesDB

31464

MeSH

D006061

[2] [3]

[4] [5]

Swyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing tumors) and a typical medical treatment would include hormone replacement therapy with female hormones.

Swyer syndrome as a form of "pure gonadal dysgenesis" There are several forms of gonadal dysgenesis. The term “pure gonadal dysgenesis” (PGD) or Monica F's syndrome has been used to describe conditions with normal sets of sex chromosomes (e.g., 46,XX or 46,XY), as opposed to those whose gonadal dysgenesis results from missing all or part of the second sex chromosome. The latter group includes those with Turner syndrome (i.e., 45,X) and its variants, as well as those with mixed gonadal dysgenesis and a mixture of cell lines, some containing a Y chromosome (e.g., 46,XY/45,X). Thus Swyer syndrome is referred to as PGD, 46,XY, and XX gonadal dysgenesis as PGD, 46,XX.[6] Patients with PGD have a normal karyotype but may have defects of a specific gene on a chromosome.

Genetic associations Types include: Type

OMIM

46,XY GONADAL DYSGENESIS, COMPLETE, SRY-RELATED

400044

46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, DHH-RELATED

233420

613080

46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH 9p24.3 DELETION

154230

Locus

[3]

SRY

Yp11.3

[7]

DHH

12q13.1

46,XY GONADAL DYSGENESIS, COMPLETE OR PARTIAL, WITH OR WITHOUT ADRENAL FAILURE 612965 [8] 46,XY GONADAL DYSGENESIS, COMPLETE, CBX2-RELATED

Gene

[9] [10]

NR5A1 9q33 CBX2

17q25 9p24.3

XY gonadal dysgenesis

Pathogenesis The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY, the sex-determining region of the Y chromosome. Mutations of SRY account for many cases of Swyer syndrome. When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY (genetically male) fetus. Without testes, no testosterone or antimüllerian hormone (AMH) is produced. Without testosterone, the external genitalia fail to virilize, resulting in normal female genitalia, and the wolffian ducts fail to develop, so no internal male organs are formed. Without AMH, the Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina). A baby who is externally a girl is born and is normal in all anatomic respects except that the child has nonfunctional streak gonads instead of ovaries or testes. As girls' ovaries normally produce no important body changes before puberty, a defect of the reproductive system typically remains unsuspected until puberty fails to occur in people with Swyer syndrome. They appear to be normal girls and are generally considered so.

Diagnosis Due to the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. As the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these persons will develop pubic hair, though it often remains sparse. Evaluation of delayed puberty usually reveals elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). Although an XY karyotype can also indicate a person with complete androgen insensitivity syndrome, the absence of breasts, and the presence of a uterus and pubic hair exclude the possibility. At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome.

Treatment Upon diagnosis, estrogen and progesterone therapy is typically commenced, prompting the development of female characteristics. The consequences of streak gonads to a person with Swyer syndrome: 1. Gonads cannot make estrogen, so the breasts will not develop and the uterus will not grow and menstruate until estrogen is administered. This is often given transdermally. 2. Gonads cannot make progesterone, so menstrual periods will not be predictable until progestin is administered, still usually as a pill. 3. Gonads cannot produce eggs so conceiving children naturally is not possible. A woman with a uterus but no ovaries may be able to become pregnant by implantation of another woman's fertilized egg (embryo transfer). 4. Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Streak gonads are usually removed within a year or so of diagnosis since the cancer can begin during infancy.

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Gonadal dysgenesis and other similar or related conditions Swyer syndrome represents one phenotypic result of a failure of the gonads to develop properly, and hence is part of a class of conditions termed gonadal dysgenesis. There are many forms of gonadal dysgenesis. Swyer syndrome is an example of a condition in which an externally unambiguous female body carries dysgenetic, atypical, or abnormal gonads. Other examples include complete androgen insensitivity syndrome, partial X chromosome deletions, lipoid congenital adrenal hyperplasia, and Turner syndrome.

References [1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ Q56. 4 [2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=752. 7 [3] http:/ / omim. org/ entry/ 400044 [4] http:/ / www. diseasesdatabase. com/ ddb31464. htm [5] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D006061 [6] Specific Disorders of Ambiguous Genitalia (http:/ / www. medscape. com/ viewarticle/ 499501_5) [7] http:/ / omim. org/ entry/ 233420 [8] http:/ / omim. org/ entry/ 612965 [9] http:/ / omim. org/ entry/ 613080 [10] http:/ / omim. org/ entry/ 154230

External links • Gonadal dysgenesis (http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997 Case Studies/N. Justus.html) • Stoicanescu D, Belengeanu V, et al. (2006). "Complete Gonadal Dysgenesis With XY Chromosomal Constitution" (http://www.acta-endo.ro/actamedica/abstract.php?doi=2006.465). Acta Endocrinologica (Buc) 2 (4): 465–70. doi: 10.4183/aeb.2006.465 (http://dx.doi.org/10.4183/aeb.2006.465).

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Tay–Sachs disease Tay–Sachs disease Classification and external resources

Cherry-red spot as seen in Tay Sachs disease: the fovea's center appears bright red because it is surrounded by a milky halo. [1]

ICD-10

E75.0

ICD-9

330.1

OMIM

272800

DiseasesDB

12916

MedlinePlus

001417

eMedicine

ped/3016

MeSH

D013661

[2] [3]

272750

[4]

[5] [6] [7] [8]

Tay–Sachs disease (also known as GM2 gangliosidosis or hexosaminidase A deficiency) is a rare autosomal recessive genetic disorder. In its most common variant (known as infantile Tay–Sachs disease), it causes a progressive deterioration of nerve cells and of mental and physical abilities that commences around six months of age and usually results in death by the age of four. The disease occurs when harmful quantities of cell membrane components known as gangliosides accumulate in the brain's nerve cells, eventually leading to the premature death of the cells. A ganglioside is a form of sphingolipid, which makes Tay–Sachs disease a member of the sphingolipidoses. There is no known cure or treatment. The disease is named after the British ophthalmologist Waren Tay, who in 1881 first described a symptomatic red spot on the retina of the eye, and after the American neurologist Bernard Sachs of Mount Sinai Hospital, New York, who described in 1887 the cellular changes of Tay–Sachs disease and noted an increased disease prevalence in the Eastern European Ashkenazi Jewish population. Research in the late 20th century demonstrated that Tay–Sachs disease is caused by a genetic mutation in the HEXA gene on (human) chromosome 15. A large number of HEXA mutations have been discovered, and new ones are still being reported. These mutations reach significant frequencies in specific populations. French Canadians of southeastern Quebec have a carrier frequency similar to that seen in Ashkenazi Jews, but carry a different mutation. Cajuns of southern Louisiana carry the same mutation that is seen most commonly in Ashkenazi Jews. HEXA

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mutations are rare and are most seen in genetically isolated populations. Tay–Sachs can occur from the inheritance of either two similar, or two unrelated, causative mutations in the HEXA gene.

Signs and symptoms Tay–Sachs disease is classified into several forms, which are differentiated based on the onset age of neurological symptoms.[][] • Infantile Tay–Sachs disease. Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as neurons become distended with gangliosides, a relentless deterioration of mental and physical abilities begins. The child becomes blind, deaf, unable to swallow, atrophied, and paralytic. Death usually occurs before the age of four.[] • Juvenile Tay–Sachs disease. Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs, and usually is initially seen in children between two and ten years old. People with Tay–Sachs disease develop cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity.[9] Death usually occurs between the age of five to fifteen years.[10] • Adult/Late-Onset Tay–Sachs disease. A rare form of this disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs - which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis.[] People with late-onset Tay–Sachs may become full-time wheelchair users in adulthood. Until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile and adult forms of the disease were not always recognized as variants of Tay–Sachs disease. Post-infantile Tay–Sachs was often misdiagnosed as another neurological disorder, such as Friedreich's ataxia.[11]

Genetics Tay–Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents are carriers there is a 25% risk of giving birth to an affected child with each pregnancy. The affected child would have received a mutated copy of the gene from each parent.[] Tay–Sachs results from mutations in the HEXA gene on human chromosome 15, which encodes the alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. By 2000, more than 100 different mutations had been identified in the human HEXA gene.[] These mutations have included single base insertions and deletions, splice phase mutations, missense mutations, and other more complex patterns. Each of these mutations alters the gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function.[12] In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations. Initial research focused on several such founder populations:

Tay–Sachs disease is inherited in the autosomal recessive pattern, depicted above.

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• Ashkenazi Jews. A four base pair insertion in exon 11 (1278insTATC) results in an altered reading frame for the HEXA gene. This mutation is the most prevalent mutation in the Ashkenazi Jewish population, and leads to the infantile form of Tay–Sachs disease.[] • Cajun. The same 1278insTATC mutation found among Ashkenazi Jews occurs in the Cajun population of southern Louisiana. Researchers have traced the ancestry of carriers from Louisiana families back to a single founder couple – not known to be Jewish – that lived in France in the 18th century.[13]

The HEXA gene is located on the long (q) arm of human chromosome 15, between positions 23 and 24.

• French Canadians. Two mutations, unrelated to the Ashkenazi/Cajun mutation, are absent in France but common among French Canadians living in eastern Quebec. Pedigree analysis suggests the mutations were uncommon before the late 17th century.[14][15] In the 1960s and early 1970s, when the biochemical basis of Tay–Sachs disease was first becoming known, no mutations had been sequenced directly for genetic diseases. Researchers of that era did not yet know how common polymorphisms would prove to be. The "Jewish Fur Trader Hypothesis," with its implication that a single mutation must have spread from one population into another, reflected the knowledge at the time. Subsequent research, however, has proven that a large variety of different HEXA mutations can cause the disease. Because Tay–Sachs was one of the first genetic disorders for which widespread genetic screening was possible, it is one of the first genetic disorders in which the prevalence of compound heterozygosity has been demonstrated.[16] Compound heterozygosity ultimately explains the disease's variability, including the late-onset forms. The disease can potentially result from the inheritance of two unrelated mutations in the HEXA gene, one from each parent. Classic infantile Tay–Sachs disease results when a child has inherited mutations from both parents that completely stop the biodegradation of gangliosides. Late onset forms occur due to the diverse mutation base – people with Tay–Sachs disease may technically be heterozygotes, with two differing HEXA mutations that both inactivate, alter, or inhibit enzyme activity. When a patient has at least one HEXA copy that still enables some level of hexosaminidase A activity, a later onset disease form occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.[] Heterozygous carriers (individuals who inherit one mutant allele) show abnormal enzyme activity, but manifest no disease symptoms. This phenomenon is called dominance; the biochemical reason for wild-type alleles' dominance over nonfunctional mutant alleles in inborn errors of metabolism comes from how enzymes function. Enzymes are protein catalysts for chemical reactions; as catalysts, they speed up reactions without being used up in the process, so only small enzyme quantities are required to carry out a reaction. Someone homozygous for a nonfunctional mutation in the enzyme-encoding gene has little or no enzyme activity, so will manifest the abnormal phenotype. A heterozygote (heterozygous individual) has at least half of the normal enzyme activity level, due to expression by the wild-type allele. This level is normally enough to enable normal function and thus prevent phenotypic expression.[]

Pathophysiology Tay–Sachs disease is caused by insufficient activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down glycolipids. When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Hexosaminidase A specifically breaks down fatty acid derivatives called gangliosides; these are made and biodegraded rapidly in early life as the brain develops. Patients with and carriers of Tay–Sachs can be identified by a simple blood test that measures hexosaminidase A activity.[]

TaySachs disease The hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate-specific cofactor for the enzyme. Deficiency in any one of these proteins leads to ganglioside storage, primarily in the lysosomes of neurons. Tay–Sachs disease (along with AB-variant GM2-gangliosidosis and Sandhoff disease) occurs because a mutation inherited from both parents deactivates or inhibits this process. Most Tay–Sachs mutations probably do not directly affect protein functional elements (e.g., the active site). Instead, they cause incorrect folding (disrupting function) or disable intracellular transport.[17]

Diagnosis In patients with a clinical suspicion for Tay–Sachs disease, with any age of onset, the initial testing involves an enzyme assay to measure the activity of hexosaminidase in serum, fibroblasts or leukocytes. Total hexosaminidase enzyme activity is decreased in individuals with Tay-Sachs as is the percentage of hexosaminidase A. After confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis can be pursued.[] All patients with infantile onset Tay–Sachs disease have a "cherry red" macula in the retina, easily observable by a physician using an ophthalmoscope.[][] This red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. The choroidal circulation is showing through "red" in this foveal region where all retinal ganglion cells are pushed aside to increase visual acuity. Thus, this cherry-red spot is the only normal part of the retina; it shows up in contrast to the rest of the retina. Microscopic analysis of the retinal neurons shows they are distended from excess ganglioside storage.[18] Unlike other lysosomal storage diseases (e.g., Gaucher disease, Niemann–Pick disease, and Sandhoff disease), hepatosplenomegaly (liver and spleen enlargement) is not seen in Tay–Sachs.[19]

Prevention Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs: • Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective gene copy from both parents. Couples are informed and may choose to have an abortion.[20] Chorionic villus sampling (CVS), the most common form of prenatal diagnosis, can be performed between 10 and 14 weeks of gestation. Amniocentesis can be performed around 15 weeks. These procedures have risks of miscarriage of 1% or less.[21][22] • Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization, it is possible to test the embryo for the disorder prior to implantation. Healthy embryos are then selected and transferred into the mother's womb, while unhealthy embryos are discarded. In addition to Tay–Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders.[23] • Mate selection. In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that couples with Tay–Sachs or another genetic disorder can avoid conception.[]

Management There is currently no cure or treatment for Tay–Sachs disease. Even with the best care, children with infantile Tay–Sachs disease die by the age of 4.[] Although experimental work is underway, no current medical treatment of the root cause yet exists. Patients receive supportive care to ease the symptoms or extend life.[] Infants are given feeding tubes when they can no longer swallow.[24] Improvements in life-extending care have somewhat lengthened the survival of children with Tay–Sachs disease, but no current therapy is able to reverse or delay the disease's progress.[] In late-onset Tay-Sachs, medication (e.g., lithium for depression) can sometimes control psychiatric symptoms and seizures, although some medications (e.g., tricyclic antidepressants, phenothiazines, haloperidol, and risperidone) are associated with significant adverse effects.[][25] In 2011, researchers have discovered that

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Pyrimethamine can increase ß-hexosaminidase activity, thus slowing down the progression of Late-Onset Tay–Sachs disease.[26]

Epidemiology Ashkenazi Jews have a high incidence of Tay–Sachs and other lipid storage diseases. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. The disease incidence is about 1 in every 3,500 newborn among Ashkenazi Jews.[27] French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of being a carrier. In the general population, the incidence of carriers as heterozygotes is about 1 in 300.[] The incidence is approximately 1 in 320,000 newborns in the general population in United States.[28] Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population: • Heterozygote advantage.[] When applied to a particular allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment.[][29]

Founder effects occur when a small number of individuals from a larger population establish a new population. In this illustration, the original population is on the left with three possible founder populations on the right. Two of the three founder populations are genetically distinct from the original population.

• Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children to replace them. This phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease.[30] • Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes[] is the result of an elevated allele frequency[] that existed by chance in an early founder population.[] Tay–Sachs disease was one of the first genetic disorders for which epidemiology was studied using molecular data. Studies of Tay–Sachs mutations using new molecular techniques such as linkage disequilibrium and coalescence analysis has brought an emerging consensus among researchers supporting the founder effect theory.[][][]

History Waren Tay and Bernard Sachs, two physicians, described the disease's progression and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms. Both Tay and Sachs reported their first cases among Jewish families. Tay reported his observations in 1881 in the first volume of the proceedings of the British Ophthalmological Society, of which he was a founding member.[] By 1884, he had seen three cases in a single family. Years later, Bernard Sachs, an American neurologist, reported similar findings when he reported a case of "arrested cerebral development" to other New York Neurological Society members.[] Sachs, who recognized that the disease had a familial basis, proposed that the disease should be called amaurotic familial idiocy. However, its genetic basis was still poorly understood. Although Gregor Mendel had published his article on the genetics of peas in 1865, Mendel's paper was largely forgotten for more than a generation – not rediscovered by other scientists until 1899. Thus, the Mendelian model for explaining Tay–Sachs was unavailable to scientists and doctors of the time. The first edition of the Jewish Encyclopedia, published in 12 volumes between 1901 and 1906, described what was then known about the disease:[] It is a curious fact that amaurotic family idiocy, a rare and fatal disease of children, occurs mostly among Jews. The largest number of cases has been observed in the United States—over thirty in

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number. It was at first thought that this was an exclusively Jewish disease, because most of the cases at first reported were between Russian and Polish Jews; but recently there have been reported cases occurring in non-Jewish children. The chief characteristics of the disease are progressive mental and physical enfeeblement; weakness and paralysis of all the extremities; and marasmus, associated with symmetrical changes in the macula lutea. On investigation of the reported cases, they found that neither consanguinity nor syphilitic, alcoholic, or nervous antecedents in the family history are factors in the etiology of the disease. No preventive measures have as yet been discovered, and no treatment has been of benefit, all the cases having terminated fatally. Jewish immigration to the United States peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in Eastern Europe; this was also a period of nativism (hostility to immigrants) in the United States. Opponents of immigration often questioned whether immigrants from southern and eastern Europe could be assimilated into American society. Reports of Tay–Sachs disease contributed to a perception among nativists that Jews were an inferior race. Reuter writes "that Jewish immigrants continued to display their nervous tendencies in America where they were free from persecution was seen as proof of their biological inferiority and raised concerns about the degree to which they were being permitted free entry into the US."[] In 1969, Shintaro Okada and John S. O'Brien showed that Tay–Sachs disease was caused by an enzyme defect; he also proved that Tay–Sachs patients could be diagnosed by an assay of hexosaminidase A activity.[31] The further development of enzyme assays demonstrated that levels of hexosaminidases A and B could be measured in patients and carriers, allowing the reliable detection of heterozygotes. During the early 1970s, researchers developed protocols for newborn testing, carrier screening, and pre-natal diagnosis.[][] By the end of 1979, researchers had identified three variant forms of GM2 gangliosidosis, including Sandhoff disease and the AB variant of GM2-gangliosidosis, accounting for false negatives in carrier testing.[]

Society and culture Since carrier testing for Tay–Sachs began in 1971, millions of Ashkenazi Jews have been screened as carriers. Jewish communities embraced the cause of genetic screening from the 1970s on. The success with Tay–Sachs disease has led Israel to become the first country that offers free genetic screening and counseling for all couples and opened discussions about the proper scope of genetic testing for other disorders in Israel.[32] Because Tay–Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (prior to polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases, and researchers sought evidence of a selective process. A continuing controversy is whether heterozygotes (carriers) have or had a selective advantage. Neil Risch writes: "The anomalous presence of four different lysosomal storage disorders in the Ashkenazi Jewish population has been the source of long-standing controversy. Many have argued that the low likelihood of four such diseases — particularly when four are involved in the storage of glycosphingolipids — must reflect past selective advantage for heterozygous carriers of these conditions."[]

Neil Risch is the principal author of a study which analyzes the geographic distributions of mutations among Ashkenazi Jews. Risch found [] "compelling support for random genetic drift."

This controversy among researchers has reflected three debates among geneticists at large: • Dominance versus overdominance. In applied genetics (selective and agricultural breeding), this controversy has reflected the century-long debate over whether dominance or overdominance provides the best explanation for heterosis (hybrid vigor).

TaySachs disease • The classical/balance controversy. The classical hypothesis of genetic variability, often associated with Hermann Muller, maintains that most genes are of a normal wild type, and that most individuals are homozygous for that wild type, while most selection is purifying selection that operates to eliminate deleterious alleles. The balancing hypothesis, often associated with Theodosius Dobzhansky, states that heterozygosity will be common at loci, and that it frequently reflects either directional selection or balancing selection. • Selectionists versus neutralists. In theoretical population genetics, selectionists emphasize the primacy of natural selection as a determinant of evolution and of variation within a population, while neutralists favor a form of Motoo Kimura's neutral theory of molecular evolution, which emphasizes the role of genetic drift.[]

Research directions Enzyme replacement therapy Enzyme replacement therapy techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat Tay–Sachs as well. The goal would be to replace the nonfunctional enzyme, a process similar to insulin injections for diabetes. However, in previous studies the HEXA enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that forms the blood–brain barrier in humans. Researchers have also tried directly instilling the deficient enzyme hexosaminidase A into the cerebrospinal fluid (CSF), which bathes the brain. However, intracerebral neurons seem unable to take up this physically large molecule efficiently even when it is directly by them. Therefore, this approach to treatment of Tay–Sachs disease has also been ineffective so far.[]

Jacob sheep model Tay–Sachs disease exists in Jacob sheep.[] The biochemical mechanism for this disease in the Jacob sheep is virtually identical to that in humans, wherein diminished activity of hexosaminidase A results in increased concentrations of GM2 ganglioside in the affected animal.[] Sequencing of the HEXA gene cDNA of affected Jacobs sheep reveal an identical number of nucleotides and exons as in the human HEXA gene, and 86% nucleotide sequence identity.[] A missense mutation (G444R)[] was found in the HEXA cDNA of the affected sheep. This mutation is a single nucleotide change at the end of exon 11, resulting in that exon's deletion (before translation) via splicing. The Tay–Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapy clinical trials, which may prove useful for disease treatment in humans.[]

Substrate reduction therapy Other experimental methods being researched involve substrate reduction therapy, which attempts to use alternative enzymes to increase the brain's catabolism of GM2 gangliosides to a point where residual degradative activity is sufficient to prevent substrate accumulation.[33][34] One experiment has demonstrated that using the enzyme sialidase allows the genetic defect to be effectively bypassed, and as a consequence, GM2 gangliosides are metabolized so that their levels become almost inconsequential. If a safe pharmacological treatment can be developed – one that increases expression of lysosomal sialidase in neurons without other toxicity – then this new form of therapy could essentially cure the disease.[35] Another metabolic therapy under investigation for Tay–Sachs disease uses miglustat.[36] This drug is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyzes the first step in synthesizing glucose-based glycosphingolipids like GM2 ganglioside.[37]

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Increasing β-hexosaminidase A activity As Tay–Sachs disease is a deficiency of β-hexosaminidase A, by getting a substance that increases its activity, people affected will not be deteriorating as fast or not at all. While for infantile Tay–Sachs disease, there is no β-hexosaminidase A so then the treatment would be ineffective. However, for people affected by Late-Onset Tay–Sachs disease, they still have β-hexosaminidase A. The drug Pyrimethamine has been shown to increase activity of β-hexosaminidase A.[] However, the increased levels of β-hexosaminidase A still fall far short of the desired "10% of normal HEXA", above which the phenotypic symptoms begin to disappear.[]

References [1] http:/ / apps. who. int/ classifications/ icd10/ browse/ 2010/ en#/ E75. 0 [2] http:/ / www. icd9data. com/ getICD9Code. ashx?icd9=330. 1 [3] http:/ / omim. org/ entry/ 272800 [4] http:/ / omim. org/ entry/ 272750 [5] http:/ / www. diseasesdatabase. com/ ddb12916. htm [6] http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 001417. htm [7] http:/ / www. emedicine. com/ ped/ topic3016. htm [8] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2013/ MB_cgi?field=uid& term=D013661 [22] N Engl J Med 2012;366:64 [28] GM2 Gangliosidoses - Introduction And Epidemiology (http:/ / emedicine. medscape. com/ article/ 951943-overview) at Medscape. Author: David H Tegay. Updated: Mar 9, 2012 [29] Tay-Sachs and French Canadians: A Case of Gene-Culture Co-evolution? (http:/ / www. scirp. org/ journal/ PaperInformation. aspx?paperID=21701), Advances in Anthropology, Vol.2 No.3, August 2012,

External links • GeneReviews/NCBI/NIH/UW entry on hexosaminidase A deficiency, Tay–Sachs disease (http://www.ncbi. nlm.nih.gov/books/NBK1218/) • NINDS Tay–Sachs Disease Information Page (http://www.ninds.nih.gov/disorders/taysachs/taysachs.htm) • Tay–Sachs disease (http://ghr.nlm.nih.gov/condition=taysachsdisease) at NLM Genetics Home Reference • Tay–Sachs on NCBI (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd. section.238)

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Interesting Information CSI effect Forensic science

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The CSI effect, also known as the CSI syndrome[] and the CSI infection,[] is any of several ways in which the exaggerated portrayal of forensic science on crime television shows such as CSI: Crime Scene Investigation influences public perception. The term most often refers to the belief that jurors have come to demand more forensic evidence in criminal trials, thereby raising the effective standard of proof for prosecutors. While this belief is widely held among American legal professionals, some studies have suggested that crime shows are unlikely to cause such an effect, although frequent CSI viewers may place a lower value on circumstantial evidence.[] As technology improves and becomes more prevalent throughout society, people may also develop higher expectations for the capabilities of forensic technology.[] There are several other manifestations of the CSI effect. Greater public awareness of forensic science has also increased the demand for forensic evidence in police investigations, inflating workloads for crime laboratories. The number and popularity of forensic science programs at the university level have greatly increased worldwide, though some new programs have been criticized for inadequately preparing their students for real forensic work. It is possible that forensic science shows teach criminals how to conceal evidence of their crimes, thereby making it more difficult for investigators to solve cases.

CSI effect

Background The CSI effect is named for CSI: Crime Scene Investigation, a television program which first aired in 2000. In CSI, a fictional team of crime scene investigators solve murders in the Las Vegas metropolitan area. In each episode, the discovery of a dead body leads to a criminal investigation by members of the team, who gather and analyze forensic evidence, question witnesses, and apprehend suspects.[]:ch.IIA The show's popularity led to two spin-offs: CSI: Miami, which debuted in 2002, and CSI: NY, first aired in 2004. The CSI franchise's success resulted in the production of many similar shows;[] in turn, the "CSI effect" has been associated with other crime shows, including American Justice, Bones, Cold Case, Cold Case Files, Cold Squad, Criminal Minds, Crossing Jordan, Exhibit A: Secrets of Forensic Science, Forensic Files, NCIS, Numb3rs, Silent Witness, Waking the Dead, Wire in the Blood, and Without a Trace.[]:ch.2[][] Based on the Nielsen ratings, six of the top ten most popular television shows in the United States in 2005 were crime dramas, and CSI: Crime Scene Investigation reached the number one ranking in November 2007.[]:ch.2 Several aspects of popular crime shows have been criticized as being unrealistic. For instance, the show's characters not only investigate ("process") crime scenes, but they also conduct raids, engage in suspect pursuit and arrest, interrogate suspects, and solve cases, which falls under the responsibility of uniformed officers and detectives, not CSI personnel. Additionally, if CSIs process a crime scene it is inappropriate for them to also be involved in the examination and testing of any evidence collected from that scene as it would compromise the impartiality of scientific evidence. In real investigations, DNA and fingerprint data is often unobtainable and, when they are available, can take several weeks or months to process, whereas television crime labs usually get results within hours.[] In the first season of CSI, technicians made a plaster mold of the interior of a wound to determine the type of knife used to make the wound, which is not possible with current technology.[] Characters on television often use the word "match" to describe a definitive relationship between two pieces of evidence, whereas real forensic technicians tend to use terms that are less definite, which acknowledges that absolute certainty is often not possible.[1] Anthony E. Zuiker, creator of the CSI franchise, claimed that "all of the science is accurate" on the shows;[] researchers, however, have described CSI's portrayal of forensic science as "high-tech magic".[] Forensic scientist Thomas Mauriello estimated that 40 percent of the scientific techniques depicted on CSI do not exist.[] In addition to using unrealistic techniques, CSI ignores all elements of uncertainty present in real investigations, and instead portrays experimental results as absolute truth.[] The notion that these inaccurate portrayals could alter the public perception of forensic evidence was dubbed the "CSI effect", a term which began to appear in mainstream media as early as 2004.[] By 2009, more than 250 stories about the CSI effect had appeared in newspapers and magazines,[] including articles in National Geographic,[] Scientific American,[][] and U.S. News & World Report.[] Although the CSI effect is a recent phenomenon, it has long been recognized that media portrayals of the United States legal system are capable of significantly altering public awareness, knowledge, and opinions of it.[2] A 2002 juror survey showed that viewers of the popular court show Judge Judy were greatly misinformed about the purpose of the judge within a courtroom.[3] Earlier programs which may have affected public perception of "the legal or investigative systems" include Perry Mason (1957–66), Quincy, M.E. (1976–83) and the Law & Order franchise (1990–present).[]:ch.4 News media reports on criminal trials, extensive internet blogging, and the successes of the Innocence Project have also contributed to the increased public awareness of forensic science.[4] Zuiker has stated that "'The CSI Effect' is, in my opinion, the most amazing thing that has ever come out of the series."[5]

260

CSI effect

Manifestations Trials The popularity of forensic crime television shows supposedly gives rise to many misconceptions about the nature of forensic science and investigation procedures among jury members.[]:ch.2 The CSI effect is hypothesized to affect verdicts in two main ways: first, that jurors expect more forensic evidence than is available or necessary, resulting in a higher rate of acquittal when such evidence is absent; and second, that jurors have greater confidence in forensic and particularly DNA evidence than is warranted,[6] resulting in a higher rate of conviction when such evidence is present.[] While these and other effects may be caused by crime shows, the most commonly reported effect is that jurors are wrongly acquitting defendants despite overwhelming evidence of guilt.[] In particular, prosecutors have reported feeling pressured to provide DNA evidence even when eyewitness testimony is available.[] In one highly publicized incident, Los Angeles District Attorney Steve Cooley blamed actor Robert Blake's acquittal on murder charges on the CSI effect. Cooley noted that the not guilty verdict came despite two witness accounts of Blake's guilt, and claimed that the jury members were "incredibly stupid".[][7] By 2005, some prosecutors had begun altering their trial preparations and procedures in an attempt to counter the CSI effect.[][] Some ask questions about forensic television viewership during voir dire to target biased jurors; others use opening statements and closing arguments to minimize the possible impact of the CSI effect, and instruct jurors to adhere to the court's standards of evidence rather than those seen on television.[] Prosecutors have even hired expert witnesses to explain why particular forms of physical evidence are not relevant to their cases.[] In one Australian murder case, the defense counsel requested a judge-only trial to avoid having DNA evidence misinterpreted by a jury.[] By 2006, the CSI effect had become widely accepted as reality among legal professionals, despite little empirical evidence to validate or disprove it.[] A 2008 survey by researcher Monica Robbers showed that roughly 80 percent of all American legal professionals believed they had had decisions affected by forensic television programs.[] New York University professor Tom R. Tyler argued that, from a psychological standpoint, crime shows are more likely to increase the rate of convictions than acquittals, as the shows promote a sense of justice and closure which is not attained when a jury acquits a defendant. The perceived rise in the rate of acquittals may be related to sympathy for the defendant or declining confidence in legal authorities.[] A 2006 survey of U.S. university students reached a similar conclusion: the influence of CSI is unlikely to burden prosecutors, and may actually help them.[] One of the largest empirical studies of the CSI effect was undertaken in 2006 by Washtenaw County Circuit Court Judge Donald Shelton and two researchers from Eastern Michigan University. They surveyed more than 1,000 jurors, and found that while juror expectations for forensic evidence had increased, there was no correlation between viewership of crime shows and tendency to convict.[] One alternate explanation for the changing perception of forensic evidence is the so-called "tech effect": as technology improves and becomes more prevalent throughout society, people develop higher expectations for the capabilities of forensic technology.[] Shelton described one instance in which a jury member complained because the prosecution had not dusted the lawn for fingerprints,[] a procedure which is impossible and had not been demonstrated on any crime show.[]:ch.7 A later study by the same authors found that frequent CSI viewers may place a lower value on circumstantial evidence, but their viewership had no influence on their evaluation of eyewitness testimony or their tendency to convict in cases with multiple types of evidence.[] Many stories about the CSI effect assume that there has been an increase in acquittal rates, though this is often based entirely on anecdotal evidence. A 2009 study of conviction statistics in eight states found that, contrary to the opinions of criminal prosecutors, the acquittal rate has decreased in the years since the debut of CSI. The outcome of any given trial is much more strongly dependent on the state in which it took place, rather than whether it occurred before or after the CSI premiere.[] A 2010 study by the University of Wisconsin–Milwaukee suggests that, while there may be a correlation between crime show viewership and a perceived understanding of DNA evidence, there

261

CSI effect was no evidence that such viewership affected jury decision making.[8] As of August 2010, no empirical evidence has demonstrated a correlation between CSI viewership and acquittal rates.[][9] One researcher suggested that the perception of a CSI effect—and of other courtroom effects, such as Perry Mason syndrome and white coat syndrome—is caused not by the incompetence of jury members, but by a general distrust of the jury system as a whole.[10]

Academia The CSI effect has influenced the manner in which forensic scientists are educated and trained. In the past, those who sought to enter the field of forensics typically earned an undergraduate degree in a science, followed by a master's degree. However, the popularity of programs such as CSI has caused an increase in the demand for undergraduate courses and graduate programs in forensic science.[] In 2004, the forensics programs at Florida International University and the University of California, Davis doubled in size, reportedly as a result of the CSI effect. However, many students enter such programs with unrealistic expectations.[11] Vocational interest in forensic science has proliferated among students in countries besides the United States, including Australia,[12] the United Kingdom,[13] and Germany.[14] The increased popularity of the forensic science program at the University of Lausanne in Switzerland has also been attributed to the CSI effect.[15] Although the increased popularity of forensics programs means there are more applicants for jobs at crime labs,[] there is some concern that these courses do not adequately prepare students for real forensics work,[]:602 as graduates often lack a firm grasp of basic scientific principles that would come from a science degree.[] Many forensics students are presented with streamlined exercises with overly clear answers, which may give them distorted perceptions of the power of forensic science.[] The Albuquerque Police Department has attempted to improve scientific literacy among future forensic scientists and jurors alike by developing a "Citizen CSI" course which familiarizes local citizens with the "capabilities and limitations of authentic forensic science techniques."[]:605 While forensic crime shows are often criticized for portraying technologies that do not exist, these may inspire inventors and research teams, as it is not uncommon for scientific innovations to be first portrayed in science fiction.[]:ch.12 In 2006, IBM and the Memphis Police Department developed software to predict crime locations and time frames, an idea from the 2002 science fiction film Minority Report.[16]

Crimes The CSI effect may alter how crimes are committed. In 2000, the year that CSI: Crime Scene Investigation debuted, 46.9 percent of all rape cases in the United States were solved by police. By 2005, the solve rate had fallen to 41.3 percent. Some investigators attributed this decline to the CSI effect, as crime shows often explain in detail how criminals can conceal or destroy evidence. Several rape victims have reported that their assailants forced them to shower or clean themselves with bleach after their assaults.[] In December 2005, Jermaine McKinney broke into a home in Trumbull County, Ohio, where he murdered two women. A fan of CSI, McKinney went to unusual lengths to remove evidence of his crime: he cleaned his hands with bleach, burned the bodies and his clothing, and attempted to dispose of the murder weapon in a lake. McKinney was eventually apprehended.[] Ray Peavy, head of the Los Angeles County homicide division, commented that, in addition to teaching criminals how to conceal evidence, crime shows may even "encourage them when they see how simple it is to get away with [it] on television."[] Others argue that shows like CSI are not having any educational effect on criminals. Max Houck, director of the Forensic Science Initiative at West Virginia University, said although CSI may be educating criminals, people who resort to a life of crime generally are not very intelligent to begin with.[] It is also possible that crime shows have the opposite effect, if attempts to conceal evidence generate more evidence. Houck gave an example of criminals who avoided licking envelopes because of the DNA in their saliva, but left fingerprints and hair samples on adhesive tape instead.[] Tammy Klein, the lead investigator on the McKinney case, said that the killings she investigates are committed by people "who for the most part are pretty stupid." Larry Pozner, former president of the National

262

CSI effect

263

Association of Criminal Defense Lawyers, argued that because people who commit violent crimes generally do not take precautions, television forensics programs are unlikely to have any effect on their behavior.[] Convicted serial rapist Jonathan Haynes forced his victims to destroy forensic evidence. He was only caught after one of his victims deliberately pulled out her own hair which was later discovered in his car, tying him to the attacks. She was inspired by watching the CSI television series.[]

Police investigations Law enforcement officers often receive inquiries and demands about their investigations that stem from unrealistic portrayals on television. In a 2010 survey of Canadian police officers, some were frustrated by these CSI-affected queries, though most saw them as opportunities to inform the public about real police work.[] New technologies and the increased public awareness of forensic science have stimulated new interest in solving cold cases and encouraged higher accountability among police investigators.[] However, the increased demand for forensic evidence can cause an unmanageable workload for forensic laboratories.[] Some crime labs process several thousand cases every year.[17][] Many law enforcement agencies have insufficient storage space for the increasing amount of physical evidence they collect.[18] In some investigations, DNA evidence is not collected simply because there is not enough space to store it properly.[19]

References

ABO blood group system The ABO blood group system is the most important blood type system (or blood group system) in human blood transfusion. The associated anti-A and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food, bacteria, and viruses. ABO blood types are also present in some other animals, for example apes such as chimpanzees, bonobos, and gorillas.[1]

History of discoveries

ABO blood group antigens present on red blood cells and IgM antibodies present in the serum

The ABO blood group system is widely credited to have been discovered by the Austrian scientist Karl Landsteiner, who found three different blood types in 1900;[] he was awarded the Nobel Prize in Physiology or Medicine in 1930 for his work. Due to inadequate communication at the time it was subsequently found that Czech serologist Jan Janský had independently pioneered the classification of human blood into four groups,[] but Landsteiner's independent discovery had been accepted by the scientific world while Janský remained in relative obscurity. Janský's classification is however still used in Russia and states of former USSR (see below). In America, W.L. Moss published his own (very similar) work in 1910.[]

ABO blood group system Landsteiner described A, B, and O; Alfred von Decastello and Adriano Sturli discovered the fourth type, AB, in 1902.[] Ludwik Hirszfeld and E. von Dungern discovered the heritability of ABO blood groups in 1910–11, with Felix Bernstein demonstrating the correct blood group inheritance pattern of multiple alleles at one locus in 1924.[] Watkins and Morgan, in England, discovered that the ABO epitopes were conferred by sugars, to be specific, N-acetylgalactosamine for the A-type and galactose for the B-type.[2][3][4] After much published literature claiming that the ABH substances were all attached to glycosphingolipids, Laine's group (1988) found that the band 3 protein expressed a long polylactosamine chain[5] that contains the major portion of the ABH substances attached.[6] Later, Yamamoto's group showed the precise glycosyl transferase set that confers the A, B and O epitopes.[7]

ABO antigens The H antigen is an essential precursor to the ABO blood group Antigen. The H locus, which is located on chromosome 19, contains three exons that span more than 5 kb of genomic DNA; it encodes a fucosyltransferase that produces the H antigen on RBCs. The H antigen is a carbohydrate sequence with carbohydrates linked mainly to protein (with a minor fraction attached to ceramide moiety). It consists of a chain of β-D-galactose, β-D-N-acetylglucosamine, β-D-galactose, and 2-linked, α-L-fucose, the chain being attached to the protein or ceramide. Diagram showing the carbohydrate chains that determine the ABO blood group The ABO locus, which is located on chromosome 9, contains 7 exons that span more than 18 kb of genomic DNA. Exon 7 is the largest and contains most of the coding sequence. The ABO locus has three main alleleic forms: A, B, and O. The A allele encodes a glycosyltransferase that bonds α-N-acetylgalactosamine to the D-galactose end of the H antigen, producing the A antigen. The B allele encodes a glycosyltransferase that bonds α-D-galactose to the D-galactose end of the H antigen, creating the B antigen.

In the case of the O allele, when compared to the A allele, exon 6 lacks one nucleotide (guanine), which results in a loss of enzymatic activity. This difference, which occurs at position 261, causes a frameshift that results in the premature termination of the translation and, thus, degradation of the mRNA. This results in the H antigen remaining unchanged in case of O groups. The majority of the ABO antigens are expressed on the ends of long polylactosamine chains attached mainly to band 3 protein, the anion exchange protein of the RBC membrane, and a minority of the epitopes are expressed on neutral glycosphingolipid.

264

ABO blood group system

Serology Anti-A and anti-B antibodies (called isohaemagglutinins), which are not present in the newborn, appear in the first years of life. They are isoantibodies, that is, they are produced by an individual against antigens produced by members of the same species (isoantigens). Anti-A and anti-B antibodies are usually IgM type, which are not able to pass through the placenta to the fetal blood circulation. O-type individuals can produce IgG-type ABO antibodies.

Origin theories It is possible that food and environmental antigens (bacterial, viral, or plant antigens) have epitopes similar enough to A and B glycoprotein antigens. The antibodies created against these environmental antigens in the first years of life can cross-react with ABO-incompatible red blood cells (RBCs) that it comes in contact with during blood transfusion later in life. Anti-A antibodies are hypothesized to originate from immune response towards influenza virus, whose epitopes are similar enough to the α-D-N-galactosamine on the A glycoprotein to be able to elicit a cross-reaction. Anti-B antibodies are hypothesized to originate from antibodies produced against Gram-negative bacteria, such as E. coli, cross-reacting with the α-D-galactose on the B glycoprotein.[8] The "Light in the Dark theory" (DelNagro, 1998) suggests that, when budding viruses acquire host cell membranes from one human patient (in particular, from the lung and mucosal epithelium where they are highly expressed), they also take along ABO blood antigens from those membranes, and may carry them into secondary recipients where these antigens can elicit a host immune response against these non-self foreign blood antigens. These viral-carried human blood antigens may be responsible for priming newborns into producing neutralizing antibodies against foreign blood antigens. Support for this theory has come to light in recent experiments with HIV. HIV can be neutralized in in vitro experiments using antibodies against blood group antigens specifically expressed on the HIV-producing cell lines.[9][10] The "Light in the Dark theory" suggests a novel evolutionary hypothesis: there is true communal immunity, which has developed to reduce the inter-transmissibility of viruses within a population. It suggests that individuals in a population supply and make a diversity of unique antigenic moieties so as to keep the population as a whole more resistant to infection. A system set up ideally to work with variable recessive alleles.[citation needed] However, it is more likely that the force driving evolution of allele diversity is simply negative frequency-dependent selection; cells with rare variants of membrane antigens are more easily distinguished by the immune system from pathogens carrying antigens from other hosts. Thus, individuals possessing rare types are better equipped to detect pathogens. The high within-population diversity observed in human populations would, then, be a consequence of natural selection on individuals.[11]

Nonantigen biology The carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. ABO antigens are found having similar roles on epithelial cells as well as red blood cells.[12][13]

Transfusion reactions For a blood donor and recipient to be ABO-compatible for a transfusion, the recipient cannot be able to produce Anti-A or Anti-B antibodies that correspond to the A or B antigens on the surface of the donor's red blood cells (since the red blood cells are isolated from whole blood before transfusion, it is unimportant whether the donor blood has antibodies in its plasma). If the antibodies of the recipient's blood and the antigens on the donor's red blood cells do correspond, the donor blood is rejected. In addition to the ABO system, the Rh blood group system can affect transfusion compatibility. An individual is either positive or negative for the Rh factor; this is denoted by a '+' or '-' after their ABO type. Blood that is

265

ABO blood group system

266

Rh-negative can be transfused into a person who is Rh-positive, but an Rh-negative individual can create antibodies for Rh-positive RBCs. Because of this, the AB+ blood type is referred to as the "universal recipient", as it possesses neither Anti-B or Anti-A antibodies in its plasma, and can receive both Rh-positive and Rh-negative blood. Similarly, the O- blood type is called the "universal donor"; since its red blood cells have no A or B antigens and are Rh-negative, no other blood type will reject it.

ABO and Rh blood type donation showing matches between donor and recipient types Donors O+ A+ B+ AB+ O- ** A- B- ABRecipients

O+

✔

A+

✔

B+

✔

AB+ *

✔

✔ ✔

✔ ✔

✔

✔

✔

✔ ✔

✔

O-

✔

A-

✔

B-

✔

AB-

✔

✔ ✔

✔

✔

✔ ✔ ✔

✔

✔

ABO blood group system

267

ABO hemolytic disease of the newborn ABO blood group incompatibilities between the mother and child does not usually cause hemolytic disease of the newborn (HDN) because antibodies to the ABO blood groups are usually of the IgM type, which do not cross the placenta; however, in an O-type mother, IgG ABO antibodies are produced and the baby can develop ABO hemolytic disease of the newborn.

Inheritance Blood groups are inherited from both parents. The ABO blood type is controlled by a single gene (the ABO gene) with three alleles: i, IA, and IB. The gene encodes a glycosyltransferase—that is, an enzyme that modifies the carbohydrate content of the red blood cell antigens. The gene is located on the long arm of the ninth chromosome (9q34). The IA allele gives type A, IB gives type B, and i gives type O. As both IA and IB are dominant over i, only ii people have type O blood. Individuals with IAIA or IAi have type A blood, and individuals with IBIB or IBi have type B. IAIB people have both phenotypes, because A and B express a special dominance relationship: codominance, which means that type A and B parents can have an AB child. A type A and a A and B are codominant, giving the AB phenotype. type B couple can also have a type O child if they are both heterozygous (IBi,IAi) The cis-AB phenotype has a single enzyme that creates both A and B antigens. The resulting red blood cells do not usually express A or B antigen at the same level that would be expected on common group A1 or B red blood cells, which can help solve the problem of an apparently genetically impossible blood group.[]

Distribution and evolutionary history The distribution of the blood groups A, B, O and AB varies across the world according to the population. There are also variations in blood type distribution within human subpopulations. In the UK, the distribution of blood type frequencies through the population still shows some correlation to the distribution of placenames and to the successive invasions and migrations including Vikings, Danes, Saxons, Celts, and Normans who contributed the morphemes to the placenames and the genes to the population.[] There are six common alleles in white individuals of the ABO gene that produce one's blood type:[14][15] A

B

O

A101 (A1) B101 (B1) O01 (O1) A201 (A2) O02 (O1v) O03 (O2)

Many rare variants of these alleles have been found in human populations around the world.

ABO blood group system

268

Genetics There are two common O alleles, O01 and O02.[16] These are identical to the group A allele (A01) for the first 261 nucleotides, at which point a guanosine base is deleted, resulting in a frame-shift mutation that produces a premature stop codon and failure to produce a functional A or B transferase. This deletion is found in all populations worldwide and presumably arose before humans migrated out of Africa (50,000 to 100,000 years ago). The second most common allele for group O (termed O02) is considered to be an even more ancient than the O01 allele. Some evolutionary biologists theorize that the IA allele evolved earliest, followed by O (by the deletion of a single nucleotide, shifting the reading frame) and then IB.[citation needed] This chronology accounts for the percentage of people worldwide with each blood type. It is consistent with the accepted patterns of early population movements and varying prevalent blood types in different parts of the world: for instance, B is very common in populations of Asian descent, but rare in ones of Western European descent. Another theory states that there are four main lineages of the ABO gene and that mutations creating type O have occurred at least three times in humans.[] From oldest to youngest, these lineages comprise the following alleles: A101/A201/O09, B101, O02 and O01. The continued presence of the O alleles is hypothesized to be the result of balancing selection.[] Both theories contradict the previously held theory that type O blood evolved earliest.

ABO and Rh distribution by country

Frequency of O group in indigenous populations around the world

ABO and Rh blood type distribution by country (population averages) Country

[17]

O+

A+

B+

AB+

O-

A-

B-

AB-

21,262,641

40.0%

31.0%

8.0%

2.0%

9.0%

7.0%

2.0%

1.0%

8,210,281

30.0%

33.0%

12.0%

6.0%

7.0%

8.0%

3.0%

1.0%

10,414,336

38.0%

34.0%

8.5%

4.1%

7.0%

6.0%

1.5%

0.8%

198,739,269

36.0%

34.0%

8.0%

2.5%

9.0%

8.0%

2.0%

0.5%

33,487,208

39.0%

36.0%

7.6%

2.5%

7.0%

6.0%

1.4%

0.5%

1,339,724,852

47.7%

27.8%

18.9%

5.0%

0.3%

0.2%

0.1% 0.03%

10,532,770

27.0%

36.0%

15.0%

7.0%

5.0%

6.0%

3.0%

1.0%

5,500,510

35.0%

37.0%

8.0%

4.0%

6.0%

7.0%

2.0%

1.0%

Population [18]

Australia

[19]

Austria

[20]

Belgium

[21]

Brazil

[22]

Canada

[23]

China

[24]

Czech Republic [25]

Denmark

ABO blood group system

269 [26]

1,299,371

41.0%

31.0%

8.0%

4.0%

8.0%

5.9%

1.2%

0.9%

[27]

5,250,275

27.0%

38.0%

15.0%

7.0%

4.0%

6.0%

2.0%

1.0%

62,150,775

36.0%

37.0%

9.0%

3.0%

6.0%

7.0%

1.0%

1.0%

82,329,758

35.0%

37.0%

9.0%

4.0%

6.0%

6.0%

2.0%

1.0%

Estonia

Finland

[28]

France

[29]

Germany

Hong Kong SAR

[30]

7,055,071 41.51% 26.13% 25.34% 6.35% 0.32% 0.17% 0.14% 0.05%

[31]

306,694

47.6%

26.4%

9.3%

1.6%

8.4%

4.6%

1.7%

0.4%

[32]

4,203,200

47.0%

26.0%

9.0%

2.0%

8.0%

5.0%

2.0%

1.0%

[33]

7,233,701

32.0%

34.0%

17.0%

7.0%

3.0%

4.0%

2.0%

1.0%

[34]

73,000,000

36.6%

32.8%

21.0%

9.0%

0.4%

0.2% 0.09% 0.03%

16,715,999

39.5%

35.0%

6.7%

2.5%

7.5%

7.0%

1.3%

0.5%

4,213,418

38.0%

32.0%

9.0%

3.0%

9.0%

6.0%

2.0%

1.0%

4,660,539

34.0%

42.5%

6.8%

3.4%

6.0%

7.5%

1.2%

0.6%

38,482,919

31.0%

32.0%

15.0%

7.0%

6.0%

6.0%

2.0%

1.0%

10,707,924

36.2%

39.8%

6.6%

2.9%

6.0%

6.6%

1.1%

0.5%

[40]

28,686,633

48.0%

24.0%

17.0%

4.0%

4.0%

2.0%

1.0%

0.3%

[41]

49,320,000

39.0%

32.0%

12.0%

3.0%

7.0%

5.0%

2.0%

1.0%

40,525,002

36.0%

34.0%

8.0%

2.5%

9.0%

8.0%

2.0%

0.5%

[43]

9,059,651

32.0%

37.0%

10.0%

5.0%

6.0%

7.0%

2.0%

1.0%

[44]

76,805,524

29.8%

37.8%

14.2%

7.2%

3.9%

4.7%

1.6%

0.8%

United Kingdom

61,113,205

37.0%

35.0%

8.0%

3.0%

7.0%

7.0%

2.0%

1.0%

[46]

307,212,123

37.4%

35.7%

8.5%

3.4%

6.6%

6.3%

1.5%

0.6%

Population

O+

A+

B+

AB+

O-

A-

B-

AB-

2,261,025,244

36.4%

28.3%

20.6%

5.1%

4.3%

3.5%

1.4%

0.5%

Iceland Ireland Israel

Korea

[35]

Netherlands

[36] New Zealand [37]

Norway

[38] Poland [39]

Portugal

Saudi Arabia South Africa [42]

Spain

Sweden Turkey

[45]

United States Country

Weighted mean

 50.0% and above   40.0–49.9%   30.0–39.9%   20.0–29.9%   10.0–19.9%   5.0–9.9% Racial & Ethnic Distribution of ABO (without Rh) Blood Types[47] (This table has more entries than the table above but does not distinguish between Rh types.)

ABO blood group system

270

PEOPLE GROUP

O (%) A (%) B (%) AB (%)

Aborigines

61

39

0

0

Abyssinians

43

27

25

5

Ainu (Japan)

17

32

32

18

Albanians

38

43

13

6

Grand Andamanese

9

60

23

9

Arabs

34

31

29

6

Armenians

31

50

13

6

Asian (in USA - General)

40

28

27

5

Austrians

36

44

13

6

Bantus

46

30

19

5

Basques

51

44

4

1

Belgians

47

42

8

3

Blackfoot (N. Am. Indian)

17

82

0

1

Bororo (Brazil)

100

0

0

0

Brazilians

47

41

9

3

Bulgarians

32

44

15

8

Burmese

36

24

33

7

Buryats (Siberia)

33

21

38

8

Bushmen

56

34

9

2

Chinese-Canton

46

23

25

6

Chinese-Peking

29

27

32

13

Chuvash

30

29

33

7

Czechs

30

44

18

9

Danes

41

44

11

4

Dutch

45

43

9

3

Egyptians

33

36

24

8

English

47

42

9

3

Eskimos (Alaska)

38

44

13

5

Eskimos (Greenland)

54

36

23

8

Estonians

34

36

23

8

Fijians

44

34

17

6

Finns

34

41

18

7

French

43

47

7

3

Georgians

46

37

12

4

Germans

41

43

11

5

Greeks

40

42

14

5

Gypsies (Hungary)

29

27

35

10

Hawaiians

37

61

2

1

ABO blood group system

271 Hindus (Bombay)

32

29

28

11

Hungarians

36

43

16

5

Icelanders

56

32

10

3

Indians (India - General)

37

22

33

7

Indians (USA - General)

79

16

4

1

Irish

52

35

10

3

Italians (Milan)

46

41

11

3

Japanese

30

38

22

10

Jews (Germany)

42

41

12

5

Jews (Poland)

33

41

18

8

Kalmuks

26

23

41

11

Kikuyu (Kenya)

60

19

20

1

Koreans

28

32

31

10

Lapps

29

63

4

4

Latvians

32

37

24

7

Lithuanians

40

34

20

6

Malaysians

62

18

20

0

Maori

46

54

1

0

Mayas

98

1

1

1

Moros

64

16

20

0

Navajo (N. Am. Indian)

73

27

0

0

Nicobarese (Nicobars)

74

9

15

1

Norwegians

39

50

8

4

Papuas (New Guinea)

41

27

23

9

Persians

38

33

22

7

Peru (Indians)

100

0

0

0

Filipinos

45

22

27

6

Poles

33

39

20

9

Portuguese

35

53

8

4

Romanians

34

41

19

6

Russians

33

36

23

8

Sardinians

50

26

19

5

Scots

51

34

12

3

Serbians

38

42

16

5

Shompen (Nicobars)

100

0

0

0

Slovaks

42

37

16

5

South Africans

45

40

11

4

Spanish

38

47

10

5

Sudanese

62

16

21

0

ABO blood group system

272 Swedes

38

47

10

5

Swiss

40

50

7

3

Tartars

28

30

29

13

Thais

37

22

33

8

Turks

43

34

18

6

Ukrainians

37

40

18

6

USA (US blacks)

49

27

20

4

USA (US whites)

45

40

11

4

Vietnamese

42

22

30

5

Mean

43.91

34.80

16.55

5.14

Standard deviation

16.87

13.80

9.97

3.41

Blood group B has its highest frequency in Northern India and neighboring Central Asia, and its incidence diminishes both towards the west and the east, falling to single digit percentages in Spain.[][] It is believed to have been entirely absent from Native American and Australian Aboriginal populations prior to the arrival of Europeans in those areas.[][] Blood group A is associated with high frequencies in Europe, especially in Scandinavia and Central Europe, although its highest frequencies occur in some Australian Aborigine populations and the Blackfoot Indians of Montana.[][] Additional sources.[48][49]

Association with von Willebrand factor The ABO antigen is also expressed on the von Willebrand factor (vWF) glycoprotein,[50] which participates in hemostasis (control of bleeding). In fact, having type O blood predisposes to bleeding,[51] as 30% of the total genetic variation observed in plasma vWF is explained by the effect of the ABO blood group,[52] and individuals with group O blood normally have significantly lower plasma levels of vWF (and Factor VIII) than do non-O individuals.[53][54] In addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the Cys1584 variant of vWF (an amino acid polymorphism in VWF):[55] the gene for ADAMTS13 (vWF-cleaving protease) maps to the ninth chromosome (9q34), the same locus as ABO blood type. Higher levels of vWF are more common amongst people who have had ischaemic stroke (from blood clotting) for the first time.[56] The results of this study found that the occurrence was not affected by ADAMTS13 polymorphism, and the only significant genetic factor was the person's blood group.

Disease association Compared to non-O group (A, AB, and B) individuals, O group individuals have a 14% reduced risk of squamous cell carcinoma and 4% reduced risk of basal cell carcinoma.[57] It is also associated with a reduced risk of pancreatic cancer.[58][59] The B antigen links with increased risk of ovarian cancer.[60] Gastric cancer has reported to be more common in blood group A and least in group O.[61] According to Glass, Holmgren, et al., those in the O blood group have an increased risk of infection with cholera, and those O-group individuals who are infected have more severe infections. The mechanisms behind this association with cholera are currently unclear in the literature. The title of the referenced article is: "Predisposition for cholera of individuals with O blood group. Possible evolutionary significance." []

ABO blood group system

273

Subgroups A1 and A2 The A blood type contains about twenty subgroups, of which A1 and A2 are the most common (over 99%). A1 makes up about 80% of all A-type blood, with A2 making up the rest.[62] These two subgroups are interchangeable as far as transfusion is concerned, but complications can sometimes arise in rare cases when typing the blood.[62]

Bombay phenotype Individuals with the rare Bombay phenotype (hh) do not express antigen H on their red blood cells. As H antigen serves as precursor for producing A and B antigens, the absence of H antigen means the individuals do not have A or B antigens as well (similar to O blood group). However, unlike O group, the H antigen is absent, hence the individuals produce isoantibodies to antigen H as well as to both A and B antigens. In case they receive blood from O blood group, the anti-H antibodies will bind to H antigen on RBC of donor blood and destroy the RBCs by complement-mediated lysis. Therefore Bombay phenotype can receive blood only from other hh donors (although they can donate as though they were type O).

Nomenclature in Europe and former USSR In parts of Europe, the "O" in ABO blood type is substituted with "0" (zero), signifying the lack of A or B antigen. In the former USSR blood types are referenced using numbers and Roman numerals instead of letters. This is Janský's original classification of blood types. It Ukraine marine uniform imprint, showing the designates the blood types of humans as I, II, III, and IV, which are wearer's blood type as "B (III) Rh+" elsewhere designated, respectively, as O, A, B, and AB.[] The designation A and B with reference to blood groups was proposed by Ludwik Hirszfeld.

Examples of ABO and Rhesus D slide testing method

Blood group O positive: neither anti-A nor anti-B have agglutinated, but anti-Rh has

Result: Blood group A positive: anti-A and anti-Rh have agglutinated but anti-B has not.

In the slide testing method shown above, three drops of blood are placed on a glass slide with liquid reagents. Agglutination indicates the presence of blood group antigens in the blood.

ABO blood group system

Universal blood created from other types, and artificial blood In April 2007, an international team of researchers announced in the journal Nature Biotechnology an inexpensive and efficient way to convert types A, B, and AB blood into type O.[63] This is done by using glycosidase enzymes from specific bacteria to strip the blood group antigens from red blood cells. The removal of A and B antigens still does not address the problem of the Rhesus blood group antigen on the blood cells of Rhesus positive individuals, and so blood from Rhesus negative donors must be used. Patient trials will be conducted before the method can be relied on in live situations. Another approach to the blood antigen problem is the manufacture of artificial blood, which could act as a substitute in emergencies.[64]

Pseudoscience Peter J. D'Adamo's book, Eat Right For Your Blood Type, offers a history of human blood type development and claims that ABO blood groups can be used to determine the proper diet for your body to maintain its proper balance, as well as to predict personality traits and disease susceptibility. No published research is referenced, indicating that the information is not supported by any scientific evidence. During the 1930s, connecting blood groups to personality types became popular in Japan and other areas of the world.[65] Additional ideas include: group A causes severe hangovers, group O is associated with perfect teeth, and those with blood group A2 have the highest IQs. Scientific evidence in support of these concepts is virtually nonexistent.[66]

References [2] [3] [4] [5] [6]

Morgan, W. T. J. & Watkins, W. M. Br. Med. Bull. 25, 30–34 (1969) Watkins, W. M. Advances in Human Genetics Vol. 10 (eds Harris, H. & Hirschhorn, K.) 1–136 (Plenum, New York, 1980) Watkins, W. M. & Morgan, W. T. J. Vox Sang. 4, 97−119 (1959). Jarnefelt, Rush, Li, Laine, J. Biol. Chem. 253: 8006–8009(1978) Laine and Rush in Molecular Immunology of Complex Carbohydrates (A. Wu, E. Kabat, Eds.) Plenum Publishing Corporation, N.Y. NY (1988) [7] Yamamoto, et al., Molecular genetic basis of the histo-blood group ABO system, Nature 345: 229–233 (1990) [8] Letter to the Editor: “Natural” Versus Regular Antibodies (http:/ / resources. metapress. com/ pdf-preview. axd?code=l2206u8gj73x3251& size=largest) Journal The Protein Journal Publisher Springer Netherlands ISSN 1572-3887 (Print) 1573-4943 (Online) Issue Volume 23, Number 6 / August, 2004 Category Letter to the Editor DOI 10.1023/B:JOPC.0000039625.56296.6e Page 357 Subject Group Chemistry and Materials Science Online Date Friday, January 07, 2005 [11] Seymour RM, Allan MJ, Pomiankowski A, and Gustafsson K (2004) Evolution of the Human ABO Polymorphism by Two Complementary Selective Pressures. Proceedings: Biological Sciences 271:1065-1072. [16] Cserti CM, Dzik WH (2007) The ABO blood group system and Plasmodium falciparum malaria. Blood 110 (7) 2250-2258 [17] CIA World Factbook (https:/ / www. cia. gov/ library/ publications/ the-world-factbook/ fields/ 2119. html) [18] Blood Types - What Are They?, Australian Red Cross (http:/ / www. giveblood. redcross. org. au/ page. aspx?IDDataTreeMenu=42& parent=30) [21] Tipos Sanguíneos (http:/ / www. hemoam. org. br/ ?secao=sangue_tipos) [23] http:/ / bloodtypes. jigsy. com/ East_Asia-bloodtypes [25] Frequency of major blood groups in the Danish population. (http:/ / www. bloddonor. dk/ index. php?id=513) [26] http:/ / bloodtypes. jigsy. com/ Europe-bloodtypes [29] de:Blutgruppe#Häufigkeit der Blutgruppen [30] Profile of Donor Demographics, Hong Kong Red Cross Blood Transfusion Servive (http:/ / www5. ha. org. hk/ rcbts/ template?series=19& article=207) [34] http:/ / bloodtypes. jigsy. com/ East_Asia-bloodtypes [37] Norwegian Blood Donor Organization (https:/ / www. giblod. no/ Modules/ Page/ viewPage. asp?modid=7324& level=7324) [39] (assuming Rh and AB antigens are independent) [47] RACIAL & ETHNIC DISTRIBUTION of ABO BLOOD TYPES (http:/ / www. bloodbook. com/ world-abo. html), BLOODBOOK.COM [48] http:/ / abobloodtypes. webnode. com/ [49] http:/ / abo-rh-bloodtypes. yolasite. com/

274

ABO blood group system [62] Blood Group A Suptypes (http:/ / web. archive. org/ web/ 20080802232301/ http:/ / www. owenfoundation. com/ Health_Science/ Blood_Group_A_Subtypes. html), The Owen Foundation. Retrieved 2008-07-01. [64] BBC (http:/ / news. bbc. co. uk/ 2/ hi/ uk_news/ england/ north_yorkshire/ 6645923. stm)

Further reading • Dean L (2005). "Chapter 5: The ABO blood group." (http://www.ncbi.nlm.nih.gov/books/bv. fcgi?rid=rbcantigen.chapter.ch05ABO). Blood Groups and Red Cell Antigens. Retrieved 2007-03-24. • Farr A (1 April 1979). "Blood group serology--the first four decades (1900--1939)" (http://www.ncbi.nlm.nih. gov/pmc/articles/PMC1082436). Med Hist 23 (2): 215–26. PMC  1082436 (http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC1082436). PMID  381816 (http://www.ncbi.nlm.nih.gov/pubmed/381816).

External links • ABO (http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system=abo) at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH • Encyclopaedia Britannica, ABO blood group system (http://www.britannica.com/eb/article-9003372/ ABO-blood-group-system) • National Blood Transfusion Service (http://www.blood.co.uk/pages/world_blood.html) • Molecular Genetic Basis of ABO (http://abobloodgroup.googlepages.com)

Hh antigen system h/h, also known as Oh[1] or the Bombay Blood group, is a rare blood type. This blood phenotype was first discovered in Bombay, now known as Mumbai, in India, by Dr. Y.M. Bhende in 1952.

Problems with blood transfusion The first person that was discovered to have the Bombay phenotype seemed to have an interesting blood type that reacted to other blood types in a way never seen before. The serum contained antibodies that reacted with all red blood cells' (RBCs') normal ABO phenotypes. The red blood cells appeared to lack all of the ABO blood group antigens plus an additional antigen that was previously unknown. Individuals with the rare Bombay phenotype (hh) do not express H antigen (also called substance H), the antigen which is present in blood group O. As a result, they cannot make A antigen (also called substance A) or B antigen (substance B) on their red blood cells, whatever alleles they may have of the A and B blood-group genes, because A antigen and B antigen are made from H antigen. For this reason people who have Bombay phenotype can donate RBCs to any member of the ABO blood group system (unless some other blood factor gene, such as Rhesus, is incompatible), but they cannot receive blood from any member of the ABO blood group system (which always contains one or more of A and B and H antigens), but only from other people who have Bombay phenotype. Receiving blood which contains an antigen which has never been in the patient's own blood causes an immune reaction due to the immune system of a hypothetical receiver producing immunoglobulins not only against antigen A and B, but also against H antigen. The most common immunoglobulins synthesized are IgM and IgG (and this seems to have a very important role in the low frequency of hemolytic disease of the newborn among non-Bombay offspring of Bombay mothers). It is very important, in order to avoid any complications during a blood transfusion, to detect Bombay phenotype individuals because the usual tests for ABO blood group system would show them as group O. Since Anti-H immunoglobulins can activate the complement cascade, it will lead to the lysis of RBCs while they are still in the circulation, provoking an acute hemolytic transfusion reaction. This, of course, cannot be prevented unless the lab

275

Hh antigen system technologist that is involved has the means and the thought to test for Bombay group.

Incidence This very rare phenotype is generally present in about 0.0004% (about 4 per million) of the human population, though in some places such as Mumbai (formerly Bombay) locals can have occurrences in as much as 0.01% (1 in 10,000) of inhabitants and 1 in a million people in Europe. Given that this condition is very rare, any person with this blood group who needs an urgent blood transfusion will probably be unable to get it, as no blood bank would have any in stock. Those anticipating the need for blood transfusion may bank blood for their own use, but of course this option is not available in cases of accidental injury since one can not always plan for injury.

Biochemistry The biosynthesis of the H antigen and the A and B antigens involves a series of enzymes (glycosil transferases) that transfer monosaccharides. The resulting antigens are oligosaccharide chains, which are attached to lipids and proteins that are anchored in the RBC membrane. The function of the H antigen, apart from being an intermediate substrate in the synthesis of ABO blood group antigens, is not known although it may be involved in cell adhesion. Fortunately people who lack of the H antigen do not suffer from any deleterious effects, and being H-deficient is only an issue if they were to need a blood transfusion because they would require H-deficient blood. The specificity of the H antigen is determined by the sequence of oligosaccharides. More specifically, the minimum requirement for H antigenicity is the terminal disaccharide Fucose-Galactose, where the fucose has an alpha(1-2)linkage. This antigen is produced by a specific fucosyl transferase that catalyzes the final step in the synthesis of the molecule. Depending upon a person's ABO blood type, the H antigen is converted into either the A antigen, B antigen, or both. If a person has group O blood, the H antigen remains unmodified. Therefore, the H antigen is present more in blood type O and less in blood type AB. Two regions of the genome encode two enzymes with very similar substrate specificities: the H locus (FUT1) which encodes the Fucosyl transferase and the Se locus (FUT2) that instead indirectly encodes a soluble form of the H antigen, which is found in bodily secretions. Both genes are located on chromosome 19 at q.13.3. - FUT1 and FUT2 are tightly linked, being only 35 kb apart. Because they are highly homologous, they are likely to have been the result of a gene duplication of a common gene ancestor. The H locus contains four exones that span more than 8 kb of genomic DNA. Both the Bombay Hh antigen system - diagram showing the and para-Bombay phenotypes are the result of point mutations in the molecular structure of the ABO(H) antigen FUT1 gene. At least one functioning copy of FUT1 needs to be present system (H/H or H/h) for the H antigen to be produced on RBCs. If both copies of FUT1 are inactive (h/h), the Bombay phenotype results. The classical Bombay phenotype is caused by a Tyr316Ter mutation in the coding region of FUT1. The mutation introduces a stop codon, leading to a truncated enzyme that lacks 50 aminoacids at the C-terminal end, rendering the enzyme inactive. In Caucasians, the Bombay phenotype may be caused by a number of mutations. Likewise, a number of mutations have been reported to underlie the para-Bombay phenotype. The Se locus contains the FUT2 gene, which is expressed in secretory glands. Individuals who are "secretors" (Se/Se or Se/se) contain at least one copy of a functioning enzyme. They produce a soluble form of H antigen that is found in saliva and other bodily fluids. "Non-secretors" (se/se) do not produce soluble H antigen. The enzyme encoded by FUT2 is also involved in the synthesis of antigens of the Lewis blood group.

276

Hh antigen system

Genetics Patients who test as type O may have the Bombay phenotype if they have inherited two recessive alleles of the H gene, (their blood group is Oh and their genotype is hh), and so they do not produce the H carbohydrate that is the precursor to the A and B antigens. It then no longer matters whether the A or B enzymes are present or not, as neither A nor B antigen can be produced since the precursor antigen H is not present. Despite the designation O, Oh negative is not a sub-group of any other group. Because both parents must carry this recessive allele to transmit this blood type to their children, the condition mainly occurs in small closed-off communities where there is a good chance of both parents of a child either being of Bombay type, or being heterozygous for the h gene allele and so carrying the Bombay characteristic as recessive. Other examples may include noble families, which are inbred due to custom rather than local genetic variety.

Hemolytic disease of the newborn In theory, the maternal production of anti-H during pregnancy might cause hemolytic disease in a fetus who did not inherit the mother's Bombay phenotype. In practice, cases of HDN caused in this way have not been described. This may be possible due to the rarity of the Bombay phenotype but also because of the IgM produced by the immune system of the mother. Since IgMs are too heavy to cross the placental barrier (like indeed the IgG do) they cannot reach the blood stream of the fetus provoking an acute hemolytic reaction.

Popular culture • In the horror manga Reiko the Zombie Shop, the character Midori Yurikawa, a friendly, but temperamental young girl who becomes homicidal when assaulted and her more malicious older sister Saki Yurikawa (who died in volume one and came back as a zombie) is revealed to be a carrier of the Bombay blood type and is searched for by Reiko after Dr. Akiyama (the doctor who watched over Midori) committed suicide by slitting her wrists. • In the cooking anime Yakitate!! Japan, Pierrot was revealed to have Bombay blood, and so was the King of Monaco, who was related to him. • In the detective anime Get Backers, the protagonists Ban and Ginji are sent on a mission to retrieve Bombay blood for a terminally ill girl named Yumiko. It is later revealed that one of the antagonists possesses the bag with the said blood type and they are forced to fight them to acquire the blood. • On the daytime soap opera General Hospital, it was believed that Monica's husband Alan could not have been the father of her child, as Alan's blood was AB, Monica's was A, and the child's was thought to be O. However, it was eventually revealed that Alan was indeed the father; he and Monica were both recessive carriers of the h gene and the baby had the Bombay phenotype.[2] • In the 2007 Telugu film Okkadunnadu, both the protagonist Kiran (Gopichand) and the antagonist mafia don Sonu Bhai (Mahesh Manjrekar) are the only two carriers of the Bombay blood type. Kiran's heart is sought after by Sonu Bhai's henchmen for an urgent heart transplant required by Sonu Bhai. • In the 2012 Japanese television drama Seinaru Kaibutsutachi, Mie Arima, who has Bombay blood, is killed by the chief nurse Yuka Kasugai with a 0+ blood transfusion while undergoing a Caesarean section. • In the 2011 Canadian TV series My Babysitter's a Vampire, Ethan, one of the main characters, is said to have H-deficient blood which the vampires of the story consider a delicacy. • In the 2012 film Get the Gringo the villain (Javi) also has Bombay Blood Group. • In the 2012 Hindi film Kahaani the main antagonist (Milan Damji) has Bombay Blood Group and this fact was one of the evidence in the thriller film. • In the new series of the manga Kindaichi Case Files, and later in the special anime episode, the case titled Legend of the Vampire had several characters with the blood type called Bombay.

277

Hh antigen system • The Stone Cold Steve Austin/Dolph Lundgren film The Package revolves around h/h blood.

References External links • Hh (http://www.ncbi.nlm.nih.gov/projects/mhc/xslcgi.fcgi?cmd=bgmut/systems_info&system=hh) at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH • RMIT University (http://www.bh.rmit.edu.au/mls/subjects/abo/resources/frequency4.htm) The Bombay, para-Bombay and other H deficiencies

278

Article Sources and Contributors

Article Sources and Contributors Introduction to genetics  Source: http://en.wikipedia.org/w/index.php?oldid=547170564  Contributors: 16@r, Aaker, Alan Liefting, Andrewjlockley, Antarctic-adventurer, Arcadian, Artichoker, AshLin, Aua, Azcolvin429, Backslash Forwardslash, Benhocking, BiT, Biosicherheit, Brandon5485, Butwhatdoiknow, Ccacsmss, ConfuciusOrnis, ContiAWB, CsDix, DMacks, Deselliers, DoctorDNA, Dr d12, Engineman, Ettrig, Eurye, Federalist51, Filll, Forluvoft, Gary King, GoEThe, GrahamColm, Harold Web, Horologium, Htfiddler, Huw Powell, Idkmybffjill27, Isarra (HG), J.delanoy, James.harris.anderson, Jaums, JohnArmagh, Johnuniq, Jonverve, Juliancolton, Kristen Eriksen, Kuyabribri, La comadreja, Leevanjackson, Little Mountain 5, Little Stupid, Locogato, Lotje, Lova Falk, Luceth, Mandarax, Mark Renier, Matriak, Minorview, Mtinker86, Naturespace, Nbauman, Nk.sheridan, Nunh-huh, Pedromelcop, Professor marginalia, RUL3R, Reinyday, RenamedUser01302013, Richard001, RodC, Ryan Postlethwaite, Seipjere, Shanel, Sintaku, Snalwibma, Starproject, Sting au, Sun Creator, SylviaStanley, T. 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the Internet, Squididdily, Stephenchou0722, Sting au, Strafpeloton2, Tail, Tarotcards, The Thing That Should Not Be, The cattr, Thehelpfulone, Thepignut, Thingg, Think outside the box, Tide rolls, Tim bates, TimVickers, Tobegreat, Tsemii, Victor Blacus, Vietbio, Vsmith, Widr, WikHead, Willking1979, Wimt, Wingman4l7, Wmasterj, Woland37, Woohookitty, Yamamoto Ichiro, Youssefsan, Zonafan39, Δ, 573 anonymous edits Chromosome  Source: http://en.wikipedia.org/w/index.php?oldid=551911593  Contributors: (jarbarf), 000sponge, 129.128.164.xxx, 168..., 2001:630:206:FFFF:0:0:3128:A, 28421u2232nfenfcenc, 2D, 2fort5r, 5 albert square, 52 Pickup, 7, ABF, Abrahami, Aceg1357, Adam Schwing, AdamRetchless, Adamrush, Adashiel, Addps4cat, AdjustShift, Adrian.benko, Agathman, AgentPeppermint, Ahmedbma, Ahoerstemeier, Ajraddatz, Ajvphilp, Akhtar Ali Khan, Alansohn, Aldaron, Ale jrb, Alexei Kouprianov, AlexiusHoratius, Alfio, Algirdasr, Allens, Altenmann, Alvestrand, Amorymeltzer, Anbu121, Anclation, Andonic, 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Article Sources and Contributors Fuchsia, Gwernol, Gwideman, HJ Mitchell, Hadal, Hair, Harrison609, Haza-w, Hdt83, Heimstern, Heron, HexaChord, Hippojazz, Hristodulo, HueSatLum, Igglebob2, Igoldste, Ihope127, Ijungreis, Ilikerps, Immunize, Insanity Incarnate, Intgr, InverseHypercube, Ioana.kruse, Iridescent, Isopropyl, It Is Me Here, Iwilcox, Ixfd64, J.delanoy, JBurkhardt10, JCO312, JWSchmidt, JYolkowski, JacobTrue, Jclemens, Jeff G., JeffreyN, Jejodaro, Jennavecia, JeromyJasper11, Jerryseinfeld, Jim1138, John Mackenzie Burke, John Millikin, John254, JohnArmagh, Johntex, Johnuniq, Johnwilson254, Jonny boy da bomb, Josh Grosse, Jovianeye, Jpablo.romero, Juanmantoya, Julia wyatt, Junglecat, Jusdafax, Just James, Jwissick, Jóna Þórunn, K95, Kablammo, Kakofonous, Kandar, Karada, KaragouniS, Keegscee, Keenan Pepper, Keeptrying, Khoikhoi, Kilom691, Kingpin13, Kinneyboy90, Kiwi128, Kmcallenberg, KnowledgeOfSelf, Knutux, Kordle69, KrakatoaKatie, Kralizec!, Kreidos, Kubigula, Kungfuadam, Kuru, Kyrocnet, Lalaman567, Lalolalo123, Lankenau, Law, LeaveSleaves, Leptictidium, Lexor, Lief222, Lights, Lilac Soul, Lipothymia, Little Mountain 5, Littlealien182, Lkent-06, Llull, Lova Falk, Lradrama, Luenlin, Luis v silva, Luna Santin, Lunakeet, Lupin, Lushiness, Luuva, Lyndell, MCTales, MER-C, MK8, Macdonald-ross, MacroDaemon, Madeleine Price Ball, Madhero88, Magnus Manske, Malcolm Farmer, Malinaccier, Mandarax, Mani1, Manop, Marcelo-Silva, MarcoTolo, Marek69, Mark Renier, MarkCBoothby, Martin451, Master of Puppets, Materialscientist, Matt Amrhein, Matthuxtable, Maurog, Maxis ftw, McSly, MegaSloth, Mejoribus, Mentifisto, Mesterharm, Methcub, Michael Hardy, Michaelas10, Miciah, Mido3692, Mikael Häggström, Mike Rosoft, Million Moments, Milosminion, Minimac's Clone, Mkrose, Mobilitydream, Mocirne, Mofi2, Moogsi, Moogwrench, Mr Stephen, Mr. Stradivarius, Mr. Vernon, MrWood, Mysid, NEMT, Nakon, NathanBeach, NawlinWiki, Nepali1, NerdyScienceDude, Neutrality, Neverquick, NewEnglandYankee, Ni,K,K,I,Ta-elements, NickW557, Nigholith, Ninly, Nougie123, NuclearWarfare, Numbo3, Nuujinn, Nwbeeson, Oakley crowther, Old Moonraker, Omegatron, OmgItsSam, Onedirection203(:, Ontyx, Opabinia regalis, Orielglassstudio, Oroso, Orphan Wiki, Oxymoron83, PDH, Parslad, Pascal666, Pass a Method, Pathh, Paulrselby, Pb30, Peak, Persian Poet Gal, Petrb, Pgan002, Phantomsteve, Phil Boswell, PhilKnight, Philip Trueman, Pinball22, Pinethicket, Plange, Plasticup, PookeyMaster, Possum, Postglock, PrestonH, Professor marginalia, Proofreader77, Psinu, Pstavroulis, Ptoniolo, Pupster21, Quadell, QueefMasterGeneral, QuiteUnusual, Qxz, R. 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280

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Article Sources and Contributors Chromosomal crossover  Source: http://en.wikipedia.org/w/index.php?oldid=543154422  Contributors: 2601:E:8940:1A:4CEB:4679:D253:381B, 777sms, ASmartKid, AThing, AdamRaizen, Adrian, Agathman, Alansohn, Aldie, Arcadian, Aris Katsaris, Audriusa, Avoided, Banus, Borgx, Brim, Bseker, Camembert, Century0, Chipmunkdavis, Chopchopwhitey, Ck lostsword, Cless Alvein, Cyw90, Dancter, Darkwind, Ditaylor, Diza, Docfaust, Dr d12, Emw, Ginsengbomb, Gringer, Guyinsb, Helios, Heron, Ihavenolife, Jesse V., Jrtayloriv, Juan922, Kanthu18ind, Ketiltrout, Kjspring1, Kpjas, Kruusamägi, La goutte de pluie, Lankenau, Lexor, Logan, Luuva, Madeleine Price Ball, Magioladitis, Marshman, MickeyK, Mikael Häggström, Mouagip, NighthawkJ, Numsgil, PDH, PierreAbbat, Pietercornelis, Pjvpjv, Polyethylen, Postdlf, Ragesoss, Rjwilmsi, Rob Hurt, Rui Silva, SamEV, Sammyj, Seans Potato Business, Serephine, Shoecream, Smack, Spykid99, Stassats, Szquirrel, Taka, Teglsbo, The cattr, TimVickers, Trurl1, Tuxedo junction, Wavelength, Wickeddude12, Widefox, Wmahan, Yone Fernandes, 102 anonymous edits Genetic recombination  Source: http://en.wikipedia.org/w/index.php?oldid=539470008  Contributors: AdamRetchless, Afdave, Amazinglarry, Arcadian, Auton1, Banus, Ben Carritt, BennettL, Borgx, Brim, Burntsauce, Chaos, Chet Ubetcha, Dennis Myts, Dgw, Diberri, Docu, Dphippard, Dr d12, Duncan295, ESnyder2, EdJohnston, Emw, Eog1916, Ettrig, Eurisko97, Ferengi, Gareth Griffith-Jones, Gringer, Hwliang, Jmundo, JohnOwens, JoshuaZ, Juergen Bode, JustinWick, Kurykh, Leptictidium, Lexor, Logan, LossIsNotMore, MacDaid, Madeleine Price Ball, Mavaddat, Michael Hardy, Mikael Häggström, Mikewax, Mmprorocic, Nadiatalent, Natisto, Newwords, NuclearWarfare, Obone, PDH, PatrickStar LaserPants, Rebekah best, RichardMarioFratini, Rjwilmsi, Ruakh, SP-KP, SamEV, Samsara, Sbeath, Sboehringer, Serephine, Slicky, Sminthopsis84, Snailwalker, SpencerThiel, Szquirrel, Taka, Theron110, Thoreaulylazy, TimVickers, Truthflux, Tsumetai, Vicarious, WAS 4.250, Williamb, Wlodzimierz, Yone Fernandes, Zeimusu, Zynwyx, Æ, 115 anonymous edits Recombinant DNA  Source: http://en.wikipedia.org/w/index.php?oldid=549791405  Contributors: 2001:700:300:1021:AC8B:2427:F60F:F692, 2602:304:AE80:5699:F436:48C8:3E46:F60D, 96well, A. 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Article Sources and Contributors Wwooter, Yworo, Zzuuzz, 124 anonymous edits Y chromosome  Source: http://en.wikipedia.org/w/index.php?oldid=551138504  Contributors: 24ip, AC+79 3888, ACSE, AD Raider, Abrech, Al-Andalus, Alteripse, Anthonyhcole, Arcadian, Archaeogenetics, Ariadne55, ArnoldReinhold, AshyRaccoon, Astronautics, Bachrach44, Banus, BeIsKr, Bender235, Billyziege, Blackmetalbaz, Bobblewik, Bomac, Bryan Derksen, CCEvo-ccrossett, CCEvo-clifforc, CMBJ, CNicol, CapitalLetterBeginning, Capricorn42, Carlangas, Cburnett, Ceejayoz, Charles Matthews, ChrisJMoor, Chrumps, Chuunen Baka, Ciosek, Clark89, CodeWeasel, CopperKettle, Craig Pemberton, Cuboarding2, Cybergoth, DMacks, Darthveda, Dbachmann, DocWatson42, Download, Drfrjenkins, Dtgriscom, DuhDun, Dysmorodrepanis, ElationAviation, EnterprisingJosh07, Equant, Eras-mus, Erik Garrison, Excirial, Eyu100, Favonian, FieryPhoenix, FlamingSilmaril, Flyer22, Forluvoft, Forzan, FrankAndProust, Fred Hsu, Fyyer, GeeOh, Geno-Supremo, Geoff, Geoffhodgson, George Church, Giftlite, Glacier Wolf, Gogo Dodo, Golfvilla, Graham87, Gwernol, Habj, Haemo, Hayabusa future, Heathead, HelenOnline, Heron, HiS oWn, Hman0, Hodgdon's secret garden, Hugozam, I am not a dog, Icairns, Idlem, Ilyanep, Infoporfin, Iulius, JNW, JRHorse, JWB, Jack's Revenge, JamesBWatson, Jblotto, Jfdwolff, Jheald, JohnArmagh, Johnuniq, Joseph Solis in Australia, Junglecat, Kakofonous, Kandar, Keenan Pepper, Kerberus13, Kharhaz, Kuanyin, La goutte de pluie, LauraSHunt, Lcawte, Leszek Jańczuk, Lexor, Lights, Liiimona, Luuva, MCTales, MacsBug, Markus Kuhn, Martarius, Mattj2, Maulucioni, Metasquares, Mhahnel, Mikael Häggström, Mikeo, Miss Madeline, Montecore's Revenge, Morganfitzp, MrOllie, Mysid, Nagelfar, Namenotek, Ngebendi, Otheus, PDH, Panda411, PaulWay, Pdcook, Pengo, Pgan002, Pmronchi, Populus, Prsephone1674, Pseudomonas, Pstanton, Psychofarm, Pwilt328, Qleem, RK, RayForma, RebekahThorn, Regford, Reinyday, Rettetast, Rewster, Ribrob, Rjwilmsi, Rob Hurt, Roberdin, Rodemont2, Ronduck, Sahands, Sarystarlight, Sasha l, SchfiftyThree, Schwallex, ScottieB, Shanes, SixBlueFish, Slowking Man, Spinningspark, Ssrunner, Steve Rozen, SteveChervitzTrutane, Stismail, Suicidalhamster, Swid, Synchronism, Syp, The cattr, Tide rolls, Tim dorf, Timc, Tnova4, Tox, Urod, Versus22, Victor Chmara, Vtghf, Ward20, Wavelength, WhatamIdoing, WiiAlbanyGirl, Woohookitty, Wouterstomp, Yahya Abdal-Aziz, Yworo, Zapbacky, 269 ,‫ כל יכול‬anonymous edits Mosaic  Source: http://en.wikipedia.org/w/index.php?oldid=548248621  Contributors: AThing, Achowat, AirdishStraus, AnnaP, Anthonyhcole, AxelBoldt, BerserkerBen, Bobo192, Celefin, Cesiumfrog, Chris Capoccia, Cloudswrest, Confussed, Cwbvb13, DSatz, Double sharp, Dougher, Dryman, Duncan, Eleassar, Esparkhu, George Church, Giftlite, Gordon L, Gpvos, Graham87, Javsav, Jfdwolff, Jimerama, Jonathan Drain, Juicy fisheye, Kgrad, KrakatoaKatie, L'Aquatique, Lavajin, LedgendGamer, Lupin, Lwollert, M1ss1ontomars2k4, Macdonald-ross, MalcolmGin, Mebden, Miagirljmw14, Michael James Boyle, Mikael Häggström, Mikmd, Mkeeslar, Morwen, MrTangent, Mrwojo, Nickersonl, Nopira, Omnipaedista, PDH, Pdcook, Pengo, Ppk80, Qrc2006, RDBrown, Ranze, Rentaferret, Rich Farmbrough, Rostowicz, Sadads, Sarefo, Sommerfeld, Spiral5800, TedE, Telfordbuck, Timc, TransControl, Ukexpat, Vbs, Vikki1965, Well-Read Red, White Shadows, Woohookitty, YakbutterT, ZeroP, 59 anonymous edits SRY  Source: http://en.wikipedia.org/w/index.php?oldid=552499593  Contributors: AD Raider, Alison, Andrew Su, Arcadian, Archer3, BD2412, Bcrowe12, Blue Danube, Bobarley, Boghog, Diberri, Doc esz, DrMicro, Dysmorodrepanis, Einbierbitte, Epolk, Forluvoft, Ganymead, Gilliam, Gpvos, Guanaco, Habj, HenkvD, Histone, Janus01, Jokestress, Keithbyrd, Kyz, Latka, Lexor, LilHelpa, Lindsay658, Lute66, Madeleine Price Ball, Malathos, MarcoTolo, MartinHarper, Mikael Häggström, Narayanese, Natrix, Ngebendi, Odinbolt, Otheus, Pinkypossible, Pres27, Pstanton, RL0919, Rich Farmbrough, Rieg, Rimibchatterjee, Rjwilmsi, Saforrest, Selphie, Shaddack, Slambo, Smettems, Swid, TedPavlic, TenPoundHammer, The Anome, The Rogue Penguin, Timc, Tye, Victor Chmara, Vivin, Vlmastra, Vojtech.dostal, WeijiBaikeBianji, Wikidudeman, Yeast2Hybrid, Zoicon5, 73 anonymous edits Barr body  Source: http://en.wikipedia.org/w/index.php?oldid=539062042  Contributors: .Koen, Ahoerstemeier, Allens, Amargnanda, Arrowsmithd1, AvicAWB, Avjoska, Banus, Bryan Derksen, Capricorn42, Christopherlin, ClockworkLunch, DBigXray, Diego Grez, Dietzel65, Diucón, Doucher, Dr. F.C. 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TutterMouse, UberCryxic, Welsh, WereSpielChequers, Wjejskenewr, Woohookitty, YassineMrabet, 254 anonymous edits Dosage compensation  Source: http://en.wikipedia.org/w/index.php?oldid=536566892  Contributors: A.Giacometti, A876, AxelBoldt, Clemmy, DisillusionedBitterAndKnackered, EncycloPetey, Jebus989, Jjsakon, Kharhaz, LilHelpa, Liuyipei, Maddendalybrokaw, PDH, Robert Brockway, WikHead, 12 anonymous edits Phenylketonuria  Source: http://en.wikipedia.org/w/index.php?oldid=552749983  Contributors: 03jmgibbens, 217.98.151.xxx, 2over0, 5 albert square, 9258fahsflkh917fas, AThousandYoung, AXRL, Abeg92, Ace of Spades, Acroterion, Acunnin, Airmos, AkiAkira, AlanWolfe, Alansohn, Alphachimp, Anambo, Andrewcardy, Anetode, Antandrus, Antonio Lopez, Apers0n, Arcadian, Aronoel, Assassasts, Ataricodfish, Atif.t2, Auric, Badseed, Bartimaeus, Beelaj., Bhadani, Bmf96, BobKawanaka, Bobo192, Borgx, Brendan19, Bribroder, Bryan Derksen, C2r, Caltas, Canada Hky, Carlo Banez, Catskul, Cburnett, Cgingold, 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edits Trisomy  Source: http://en.wikipedia.org/w/index.php?oldid=548650355  Contributors: Ahauber, Alansohn, Anthonyhcole, Arcadian, Brucsterking, Daa89563, Dante Alighieri, DerHexer, Ego White Tray, Enviroboy, EoGuy, Facts707, Gadfium, Graham Chapman, Greenrd, Guido del Confuso, Headbomb, Hu12, Ilikeverin, ImperatorExercitus, Infoporfin, Jj137, Jose Ramos, Katemcelliot, Korath, LeadSongDog, Lexor, Logan, Lova Falk, Lunchscale, Luvcraft, MONGO, Mobination, Naught101, Nunh-huh, PDH, Philip Trueman, PierreAbbat, Quickmythril, RTaptap, Rjwilmsi, Robodoc.at, Sav vas, Shadowjams, Sharkford, Shinynecrid69, Sigma-w, Silverhalide, Skydeepblue, Smjg, Stevertigo, Stone, Tcncv, Tdadamemd, Ted Longstaffe, The Thing That Should Not Be, The cattr, ThespisTx, Trisomyadvocacygroup, WSGene, Warren Dew, WhatamIdoing, 73 anonymous edits Chromosome abnormality  Source: http://en.wikipedia.org/w/index.php?oldid=550951529  Contributors: Abmac, Aitias, Arcadian, Banus, Bingobangobongoboo, Bonewah, Calimo, Cptmurdok, DSBorgaonkar, DeadEyeArrow, Dekisugi, Epbr123, Excirial, Facts707, Filip kocha małgosię, Fomalhaut76, Forluvoft, Fvasconcellos, Gamewizard71, InverseHypercube, Iridescent, Its42seconds, Ixfd64, Jakob Theorell, Jelle.k, Jennes83, Jhalewood, Joey Droll, Kalielizabethx, Kingpin13, Lepidoptera, Mandarax, Marek69, Martarius, Mathonius, Matt Adore, Michael Devore, Mifter, Misterbister, Mr. Stradivarius, Neechalkaran, Niopppmmoppp, PDH, Penpen, Retama, Sceptre, Seanette, Shadowjams, Shell Kinney, Sigma-w, Skittleys, Skydeepblue, Some jerk on the Internet, Spaceflower, Spinach Dip, Stwalkerster, Tdadamemd, Tgeairn, The Thing That Should Not Be, The cattr, TimVickers, Tommerup, Whoop whoop pull up, Wtmitchell, Zephyris, 110 anonymous edits Chromosomal translocation  Source: http://en.wikipedia.org/w/index.php?oldid=543774412  Contributors: 13en, Allens, Arcadian, Aymatth2, Bility, Brim, CLW, Ccastill, Cohesion, Courcelles, Craigy144, Crystallina, Dcirovic, Dcljr, DerHexer, 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Article Sources and Contributors TedE, The Earwig, The Thing That Should Not Be, The cattr, The wub, TheGerm, Thingg, Tiddly Tom, Tommy2010, TooHuge, Tslocum, Ukexpat, UnseemlyWeasel, Upmc1234, Vcmartin, Vermin Empire, Versus22, Vidor, Violetriga, Vivin, Vrenator, Waggers, Wagino 20100516, WarthogDemon, Was a bee, Wellparp, WhatamIdoing, WhiteDragon, Widefox, WikipedianMarlith, Wikipelli, WillMcC, William Graham, Willking1979, Wimt, Wintonian, Wouterstomp, WurmWoode, X!, Xanzzibar, Xnuala, Y, Yahya Abdal-Aziz, Zachery6271995, Zchats, Zedla, Zerbey, Zigger, Zoarfy, 1076 ,55‫ דוד‬anonymous edits Down syndrome  Source: http://en.wikipedia.org/w/index.php?oldid=552875003  Contributors: *jb, -Reaper-, 1234die, 16@r, 1812ahill, 1pezguy, 24870b, 4twenty42o, 97198, A Softer Answer, A bit iffy, A1234, A3r0, AAABoy, AEMoreira042281, AMac2002, Aaron Schulz, Aaroncrick, Abdikhan, Academic Challenger, Acalamari, Acc Tee, Adam Bishop, Adam Zivner, Adamiris00, Adamrush, Addshore, Adrian J. Hunter, Adron09, Against the current, Agne27, Ahoerstemeier, Aitias, Alai, Alasdair MacIntyre, Aldy, Ale jrb, Alex.tan, AlexR, AlexiusHoratius, Alexllew, Alfie66, Algebraist, Ali K, Alison, Allison Stillwell, Allstarecho, Altenmann, Alteripse, Amandajm, AmiBebbington, Amire80, Andonic, Andrew Norman, Andrij Kursetsky, Andycjp, AnemoneProjectors, Angeles mk2, Angelic Wraith, Anilbarrat, Animum, Anomalocaris, Anonymous Dissident, Anonymous3190, Antaeus Feldspar, Antandrus, Antonio Basto, Apers0n, Apeurosucks, AppleJuggler, Aptapathy, Aranel, Arbor to SJ, Arcadian, ArielGold, Arteitle, Ascidian, Asenine, Assasin Joe, Aster Selene, At800, AuburnPilot, Aude, Augurar, Auric, AvalonX, AxelBoldt, Axxelion, AySz88, B, B0bSag3t, Baby eleanor, Babylon pride, Badgernet, Ballsofkudzu, Bantosh, Barneyg, Barry m, Bbriggs1, BeadleB, Beaudoin, Beggarsbanquet, Ben Ben, Benc256, Bender235, Benklop, Benwildeboer, Berny bernski, Betacommand, Bfrposh, Bhny, BiT, Bidgee, BigFatBuddha, BigHaz, Bigbadbrownybadger, Bigbluefish, Bill37212, Billtheking, Bingobangobongoboo, Biruitorul, Bkonrad, BlackJava, BlackRaspberry, BlastOButter42, Blastwizard, Bloodofox, Blueiris, Boatgoodies, Bob2563, Bobbykelley12, Bobchinsky, Bobo192, Bodnotbod, Bongwarrior, BookSquirrel, Boredzo, Borgx, Borisblue, Brandonhard, Brenont, Brewcrewer, Brian0918, Brian1979, Brianga, Bridies, Brighterorange, Briguy52748, BrokenSegue, Brooklyn Eagle, Brossow, Bryan Derksen, Buchanan-Hermit, Buddhipriya, Buffalo125, BullRangifer, Bullytr, Burnedthru, Burntsauce, Buttfink, Bwthemoose, Byrial, Bzuber89, C.Fred, CHMSchool, CIreland, Cadiomals, Caitens01, Calliopejen1, Can't sleep, clown will eat me, Canada Hky, Canadian-Bacon, Canderson7, Captain-n00dle, Carcharoth, Cardcapturs, Carlwev, CarolGray, Casey Abell, Cateslater, Caulde, Ccacsmss, Ccouch6, Centerone, Centrx, Ceoddyn, Cforrester101, Cgingold, Chaheel Riens, Chaldor, Chaojoker, Charles, CharlesIsEmo, Chaser, Cherryfart, Cherylchase, Chill doubt, Chinju, Chinless, Chitrapa, Chochy, Chris Bainbridge, Chris Henniker, Chrislk02, Christianbro, ChristinaDunigan, Christopher Parham, Chriswiki, Chromis, Chunkeykiller, Churn and change, CiaPan, Cinik, Circumspice, Citicat, Clackmannanshireman, Clasqm, Closedmouth, CloudSurfer, Cmbrose, Cmdrjameson, Co0lChlnX, Cockneyite, Codetiger, Coffee, Colin, Colonies Chris, Combsbr, Cometstyles, CommonsDelinker, CompRhetoric, Comscout, Conversion script, Coolguy4evur, Coolpatj, CopperSquare, Cornellrockey, Corporal butters, Correogsk, Corvus cornix, CowboySpartan, CrashWire, Craskermasker, Crazycomputers, Crazysane, Creat0r, Cristian Cappiello, CrnaGora, Ctx14, Cubic Hour, Cybercobra, CyrilB, DAJF, DARTH SIDIOUS 2, DJ Clayworth, DVD R W, Dagonchicken, Dahamu, Dandelions, DanielCD, Dantheman531, Dar-Ape, DarkFalls, Darkstell11, Darry2385, Davewild, David Woolley, David.Monniaux, DavidBrooks, DavidFarmbrough, Davidhorman, Dawka, Daycd, Daydream believer2, Dcooper, DeAceShooter, Deadeasy, Deckiller, Dedobaba3, Dedtr9, Delanyhasredhair, Delldot, Delldot on a public computer, Demmy, DerHexer, Deselliers, Desertson, Dew12, Dexter prog, Dffgd, Dgw, Diamonddavej, Dignan00, Dina, Dinferno, Diomidis Spinellis, Dipics, Discospinster, Dispenser, Dlohcierekim, Dolladollabill, Dolovis, Dom Kaos, DominikHoffmann, Donarreiskoffer, Doodledoo, Doodoggy, Down's Heart Group, Downwards, DrKiernan, Dragonbones, DragonflySixtyseven, Dukeofomnium, Dunemaire, Dutchmonkey9000, Dycedarg, Dylan Lake, EEMIV, EJF, ERoberson, ESkog, Eastlaw, Eatcacti, Ebay3, Ed g2s, Edburke317, Edward, Edwtie, Eenu, Egg Centric, Eighty8s finest, Eleassar, Electric Napalm, Eleventh1, Eli lilly, Eliahna, Elinnea, ElinorD, Elipongo, Elkman, Elockid, Elrondaragorn, Emersoni, Emmet b, Empty Buffer, Enrico Dirac, Entohaelo, EoGuy, Epbr123, Ephert, Eposty, Equazcion, EronMain, Esperant, Eternal Elder, Etr52, Eubulides, Eucalyptus grandis, Evansm2, EvelinaB, Everyking, Excalibur, Excirial, F. 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Article Sources and Contributors Capricorn42, Carolfrog, Catywalk, Cetona08, Chr18, Chris the speller, CommonsDelinker, Cool Blue, Countincr, Cureden, Dantheman531, Darth Panda, DeLarge, Dean1970, Deathinyoureheart43, Debresser, Dekisugi, Delldot, Dillonrigby, Dudester11, Dwayne, Dysepsion, Eassin, Elkman, Epbr123, Etr52, Fagballs123469, Fred Bradstadt, FreplySpang, G2gbrb, GB fan, Gadfium, Graham87, Green caterpillar, Gwernol, Gzkn, Headbomb, Hede2000, Hu12, IGod, J.delanoy, JHunterJ, Janice88Jones, Janolder, Jauerback, Jennes83, Jennifer robbins, Jennyrobbins, Jetman, Jj137, Jmh649, Joie de Vivre, Jonathan.s.kt, Jshgillis, Juliancolton, Karl-Henner, Keilana, Kgrad, KnowledgeOfSelf, Krawi, Ksu6500, Kungfuadam, LOL, LizardWizard, MC10, MPerel, Mannerssarah, Marek69, Mc1998, Mentifisto, Merope, Mickdawg, Mitico, Mr Stephen, Muhandes, Muriel Gottrop, Mushroom, My Core Competency is Competency, My name, Navidb, Neutrality, Nightstallion, Notreallydavid, Nubiatech, Oda Mari, Odie5533, Ohnoitsjamie, Omgitsyeboi, Oo7565, OverlordQ, PDH, Palecur, Pap26, Patho, PatrickStar LaserPants, Pb30, Philip Trueman, PhilipO, Piano non troppo, Piwipen, Plenumchamber, Poetdancer, Prl60, Quarl, Quickmythril, Quinxorin, Renice, Rich Farmbrough, Rillian, Rob Parrilla, Ronhjones, Saku kodo, Sam Hocevar, Sceptre, Scott Roy Atwood, Secretlondon, Setanta747 (locked), Shadowjams, Shirik, Sionus, Skydeepblue, Slakr, SmartyBoots, Solomonfromfinland, Storm Rider, Talon Artaine, Tanis118, TedE, The Anome, The Rambling Man, The Wild Falcon, The gr8 1, The sock that should not be, Thingg, Thue, Tntdj, Tohd8BohaithuGh1, Tolly4bolly, Tpbradbury, Travelbird, Treasurehouse, Trisomyadvocacygroup, Tsauce32, Typochimp, Unfree, Vegaswikian, Veronika Stolbikova, Versus22, Vjmiller1158, WHeimbigner, WSGene, Walor, West.andrew.g, Willking1979, Zipcedric, Zouavman Le Zouave, Zzuuzz, 448 ,55‫ דוד‬anonymous edits Patau syndrome  Source: http://en.wikipedia.org/w/index.php?oldid=544922399  Contributors: A5b, AStudent, AaronM, Ahauber, Ahoerstemeier, Alansohn, Alex.tan, Alhutch, Allens, Amorfati84, Andrew73, AnonMoos, Arakunem, Arcadian, Aristiana, BD2412, Betacommand, Biosthmors, Bobo192, Bookworm1973, Boromir123, Bryan Derksen, Bsirutis, Bticho, Cablehorn, Can't sleep, clown will eat me, Captain panda, Catywalk, Cenarium, Computerdan000, Czupirek, Da10g, DallasNewsweb, David Oliver, Dcandeto, Dcljr, DeBeerzerker, Download, Dungodung, Edward321, Eman2129, Enviroboy, Epbr123, Excirial, FCSundae, Filip kocha małgosię, Fythrion, Gadfium, Gaudio, Giftlite, Gilliam, Glane23, Gnowor, Greglinch, H2g2bob, Harland1, Headbomb, Healthykid, Hede2000, Hu12, Husond, J04n, Jaggedcow, Janice88Jones, Jaydisope, Jennifer robbins, Jennyrobbins, Jerimint, Jetman, Jmanigold, Johnwalker74, Jok2000, Jshgillis, Julesd, Juliancolton, Kungfuadam, LAX, LOL, Lax29, Limbic00, Lol532, Lollorz, Lugia2453, Lwt13, Magnus Manske, Mannerssarah, Marudubshinki, Mathrick, Matthewprc, Mcstrother, Meesheek, Mentifisto, Mentisock, Mgiganteus1, Michigan Roustabout, Mikael Häggström, Mjs1991, Momoricks, Mononomic, Nascar605, Natl1, Ncphillips, Nephron, Novangelis, Nwbeeson, Ocellicyst, Odin of Trondheim, Ohnoitsjamie, PDH, Pampas Cat, PedEye1, Ph.eyes, Pharaoh of the Wizards, Philip Trueman, Piano non troppo, Plenumchamber, PrimeHunter, Prosfilaes, Quickmythril, Redrocket, Renice, Reywas92, Rjsn272, Rklawton, SamRushing, Sceptre, Serrin, ShakingSpirit, SheepNotGoats, Shmget, Sidious1701, Skagedal, Slightsmile, Snowolf, Spondoolicks, SunOfErat, Syphondu, TBHecht, Talon Artaine, Tameeria, Teles, The wub, ThereseAnn, ThereseAnn13, Tohd8BohaithuGh1, Tom harrison, Trisomy13Archive, Trisomyadvocacygroup, Tristanb, Trut-h-urts man, Typochimp, Unique-ish, Velella, Veronika Stolbikova, Versus22, Wasell, Wikimandia, Wjw0111, Wouterstomp, Wuzur, Zipcedric, 340 ,55‫דוד‬ anonymous edits Cat eye syndrome  Source: http://en.wikipedia.org/w/index.php?oldid=544810988  Contributors: Alansohn, AmandaK1389, Amrush, Arcadian, Beno1000, Brownings, Bwpach, Capricorn42, Cfuse, Conti, Corinne68, Cyanolinguophile, Discospinster, Doctor82, DutchDevil, Enzo Aquarius, ErikvanB, Gilliam, Guessing Game, Headbomb, Holme053, I-love-graffiti, IspinIm, Jacek FH, Julia W, Kaushal mehta, Mentifisto, Open scientist, P motch, Ph.eyes, Philip Trueman, Plenumchamber, Posible2006, Quickmythril, Rich Farmbrough, Rjwilmsi, Rytyho usa, Snigbrook, ZooFari, 54 anonymous edits Cri du chat  Source: http://en.wikipedia.org/w/index.php?oldid=553236123  Contributors: A3RO, AJR, Abmac, Addboyhyperkid, Adrian, Aitias, Ajoust, Alansohn, Albmont, Alison, Allens, Allstarecho, Alucard (Dr.), Andonic, Arcadian, Arrkhal, Atomicfiction, Attakmint, Avoided, Beetstra, Bobo192, Boing! said Zebedee, Bped1985, Brendandagys, CL, Caltas, Capricorn42, Centrx, Chaldean, Chris the speller, Chzz, Courcelles, Cusop Dingle, Cyclonenim, DVdm, Dabbler, Dah31, Dan D. Ric, Dan493, Danielecavari, Dark Mage, Darkheroboy, Deepu poranki, Defender of torch, Dendlai, DerHexer, Dgw, Dillard421, Discospinster, Dolphonia, Draeco, Drogden, Dusty777, E2eamon, ESkog, Eastlaw, Elcobbola, Elcuco12, Electraplatypus, Enviroboy, Epbr123, Eric-Wester, Escape Orbit, Esparkhu, EvilOverlordX, Excirial, Eyesnore, Favonian, Fayenatic london, Fifo, Flapdragon, Fraggle81, Fuzbaby, Fæ, GD 6041, Gadfium, Gangster999, Gfoley4, Gman160, Gollumus, Graham87, GregorB, Gurch, Hairy Dude, HamatoKameko, HexaChord, Hoernigs, Hotcrocodile, Hsuicide, Hu12, Ihmeidan, Iijoco, Iohannes Animosus, Ispelled, J.delanoy, Jackson Peebles, Jennavecia, Jennifermccullough1, Jetman, Jfdwolff, Jhoopie, John Reaves, Jstreetley, Jusdafax, Karlthegreat, Kartano, Katalaveno, Katemend, Kbdank71, Keegan, Keenan Pepper, Khvalamde, Kinggeedorah, Kralizec!, Ktotam, Kurtis, La goutte de pluie, LeaveSleaves, Leflyman, LinDrug, LittleOldMe, Liyang, Losersalwayswin, Luboogers25, Lunchscale, MER-C, MHillyard, Mannerssarah, Marek69, Maria Larsson, Martin451, MastCell, MaxEspinho, McGeddon, Mike Rosoft, MikeDockery, MikeLynch, Misza13, Mmyers1976, Mr Rookles, Mr flea, MrsPeterWentzz13, MuZemike, MuanN, MyNameIsNotBob, NawlinWiki, NewEnglandYankee, Nibuod, Nivix, Noctibus, Nunh-huh, Ohhtouche, Onorem, Openmouth, Oxymoron83, Patrickdavidson, Paul A, Phi beta, PhiLiP, Philip Trueman, Pmj, Pol430, Prosfilaes, RA0808, RDBrown, RainbowOfLight, Rajah, Rallette, Rasmohamed, RealDealRacer, Rich Farmbrough, Richard001, Rjwilmsi, Robbit, Ronhjones, Ryan37, Samtheboy, Scapler, Sceptre, Schlice, Seaphoto, Shirik, Shoessss, Shotfirst, Sicooray, Silverlight318, Sintaku, Smiles Aloud, Some jerk on the Internet, Sosomary, Spiterus, Staffwaterboy, Stephenb, Steveking 89, Steven Zhang, Stevenfruitsmaak, Stwalkerster, Syvanen, THF, Tad Lincoln, Tbone55, TedE, TexasAndroid, The Thing That Should Not Be, Theopolisme, Timc, Tripletrex, Turgan, Twsx, Typochimp, Uirauna, Uncle Dick, User aaqib12, Utcursch, Vary, Vendettax, WSGene, Werdan7, Western Pines, Wetman, Widr, WikHead, Wikipelli, Willking1979, Wouterstomp, WriterHound, Wuhwuzdat, Xcentaur, Xchbla423, Yossiea, Ytrewq67, ZX81, Zidanie5, 617 ,55‫ דוד‬anonymous edits Klinefelter's syndrome  Source: http://en.wikipedia.org/w/index.php?oldid=529187060  Contributors: (jarbarf), 16@r, 2004-12-29T22:45Z, 62.253.64.xxx, 92anonymous92, A little insignificant, ABF, AThing, Achlysis, Admiral Norton, Aergoth, AgentPeppermint, Ahoerstemeier, Ajraddatz, Al1encas1no, Alansohn, Alex.tan, AlexR, Alison, Alkaline19, Allstarecho, Alteripse, Amatulic, Andrew Gray, Andrew73, Angela, Angelito7, Angr, Aplasia, Arcadian, ArchStanton69, Arisa, Aristiana, Armaced, Asdfgh1235, Asdfjlk123, Avb, AxelBoldt, Bemoeial, Bender235, Benji15, Bensin, BlackTooth93, Blueandred13, Bobbis, Bobo192, Bobzena bobson, Boing! said Zebedee, Brandizzi, Bratsche, BrianGCrawfordMA, Brianga, Brianriceca, Bryan Derksen, Can't sleep, clown will eat me, Capricorn42, Ceranthor, Cgingold, 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Headbomb, Heartpox, Hede2000, Hengsheng120, Henrygb, HereToHelp, Hersfold, Hhhshdfdsjfhdsfhfh, HiS oWn, Homelessboxman, Hoverflysmiles, Hydrargyrum, I dream of horses, IRP, Ianthegecko, IceKarma, Ijon, Imjustmatthew, Inarchus, InvictaHOG, Isomorphic, It Is Me Here, J.delanoy, JNW, Jablair51, Jac16888, JackBaker1995, Jacottier, Jadest, Jalamat, JamesBWatson, Jargoness, Jeff G., Jerry8311, Jfdwolff, Jim10701, Jim1138, Jimduck, Jj137, Jmh649, Joie de Vivre, Joshannon, JoshuaZ, Jsorr, Jtlawrie, Jusdafax, Jussomeguy, Karada, Keenan Pepper, Kehrbykid, Kelson, Kevin Saff, Kingpin13, Klinefelter, KnowledgeOfSelf, Koyaanis Qatsi, Kurzon, LOL, Larsklintwallmalmqvist, Lasewicz, Joe, LeaveSleaves, Leslie Mateus, LibLord, Lonelydarksky, Lotje, MC10, MJ94, MKoltnow, MPerel, Madhero88, MagneticFlux, MalcolmGin, Mannerssarah, Marcel31, Marcus Qwertyus, MarcusLeDain, Martin451, Materialscientist, Mav, Maxis ftw, Mba123, Megaman en m, MelbourneStar, Mendaliv, Mentifisto, Metasquares, Mgiganteus1, 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2004-12-29T22:45Z, Aaron Schulz, Abriffa, AdaL, Adavidb, Ahoerstemeier, Aidan Kehoe, Aisnapdragon, Aissg, AlexR, Alison, Altenmann, Alteripse, Amorymeltzer, Andres, Andrew c, Angelito7, AnnaP, Aquaprism, Arcadian, Arch dude, Ary29, Asarelah, BD2412, Bejnar, Boghog, Bryan Derksen, CDN99, Canterbury Tail, Carissa boner, CastorOilRocks, Celsiana, Cgingold, Chamal N, Chbse, Ching-3, Chowbok, Chris Capoccia, Christopherlin, Clerks, CommonsDelinker, Cristina299792458, Crypticone, Cymru.lass, DabMachine, Daira Hopwood, Damian Yerrick, DanB DanD, Daniel Mietchen, David Gerard, DeadEyeArrow, Delldot, Diberri, Dictabeard, Djdole, Drk, Dt3783, EagerToddler39, Edgar181, Edward, Ekem, Epbr123, Fg68at, Filip en, Freethyroxine83, Frietjes, Fuzbaby, G Clark, Gadfium, Gbeacock, Gcgmd, Gfmer, Gghjournal, Girl90210, HandThatFeeds, Hu12, Imysworld, Jacoplane, JamesAM, Jcw69, Jfdwolff, Jmh649, Jonathan.Marcus, Juliancolton, JulieADriver, Jushi, Just Another Dan, KX36, Kairnaola, Kate, Kgallagher11, Kim Meyrick, Kimiko, Kjkolb, Ksaviano, Kuru, Lambiam, Lenny Kaufman, Lexicon, LilHelpa, M1ss1ontomars2k4, Marek69, Markiewp, Mary Larade, Minghong, Mirmillon, Misoel, Mkrose, Mlleangelique, Moe33, Morwen, Muhandes, Nainrs, Next Paige, Noclevername, NormalAsylum, Nurg, OHM3GA, Oatmeal batman, OldakQuill, Omicronpersei8, PDH, Pacaro, PaleWhaleGail, Phil Sandifer, PierreAbbat, PonyToast, Prolog, Protonk, RG2, RVJ, Ranchgrl95, RebekahThorn, Renice, Reswobslc, Rhys, Rich Farmbrough, Rjwilmsi, Ronz, Ryan Reich, SCEhardt, SarekOfVulcan, Sbmehta, Scooter62986, Shanes, Skm12, Someguy1221, Someone else, Sonia, Squids and Chips, Superm401, THEN WHO WAS PHONE?, Tabledhote, Tameeria, Tarquin, TestPilot, The Hybrid, Theda, Tiluser, TimBentley, Topbanana, Triona, Twinpinesmall, UtherSRG, Velps, WhatamIdoing, Woohookitty, Wouterstomp, Wwallacee, 191 anonymous edits XX male syndrome  Source: http://en.wikipedia.org/w/index.php?oldid=541386942  Contributors: Alison, Arcadian, Blue Danube, Catsmeat, Chromaticity, Colincbn, Conebone6699, DivaNtrainin, Dreambeaver, Drooling Sheep, Full Shunyata, Humane doctor, Istrancis, James5200, Juhachi, Justforasecond, Michalis Famelis, Mikael Häggström, Monni95, Mr Tan, Nihola, PieRRoMaN, Qrc2006, Riana, Rjbesquire, Rjwilmsi, Scottalter, Simeon H, TedE, Typochimp, Varlaam, Wereon, Wouterstomp, Xyzzyplugh, Yonskii, Ztobor, 32 anonymous edits

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Article Sources and Contributors XY gonadal dysgenesis  Source: http://en.wikipedia.org/w/index.php?oldid=551895966  Contributors: 2004-12-29T22:45Z, AdrianLozano, Aegith, Alteripse, Arcadian, Aristiana, Beaglekeenans, Carolfrog, CastorOilRocks, Corvus.ag, Dcoetzee, Diberri, Dysfunction, Ehudzel, Ekem, Erik Baas, Ethan, Filip kocha małgosię, Headbomb, Infoporfin, MacsBug, Materialscientist, Miagirljmw14, NetRolller 3D, Now3d, Odie5533, Panda411, Phil Sandifer, Pigman, Qrc2006, RDBrown, RJASE1, Rich Farmbrough, Rimmington01, Rjbesquire, Robodoc.at, Rrostrom, Taylornw, The Anome, Yahya Abdal-Aziz, 29 ,55‫ דוד‬anonymous edits Tay–Sachs disease  Source: http://en.wikipedia.org/w/index.php?oldid=553088600  Contributors: 5 albert square, A930913, Abe Hak, Action Jackson IV, Adams177, Adashiel, Aitias, Akhristov, Alansohn, Alex.tan, Alex43223, Alexf, Alexultima, Alison, Allens, Allstarecho, Altairisfar, Amatulic, Andonic, Andrei S, Angelus Delapsus, Angr, Ann Stouter, Anonymous editor, Antandrus, Ante Aikio, Antonio Lopez, Apers0n, Aprock, Arcadian, Arthena, Avish2217, Avoided, Axeman89, Axl, Azoreg, Basawala, Bender235, Benjamin9832, Bethany1011, Biosthmors, Blue520, Bobnorwal, Bobo192, Bobsd, Boing! 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Harmonik, Nageh, Necrothesp, Nikkimaria, OGoncho, Orang Hutan, OrangeDog, Oscarthecat, P. S. Burton, PRRfan, Parsecboy, Pewwer42, Piledhigheranddeeper, Postdlf, Psinu, Quatrevingtsix, R'n'B, Radagast83, Rambam rashi, RattleMan, Receptacle, Reedy, Rjwilmsi, Roscelese, Rossumcapek, Ruhrfisch, S Whistler, SMcCandlish, Saikiri, Sandtiger, Sasata, Schwnj, Seanmilloy, Shumdw, Snowmanradio, Spidey104, StarryEyes, Sue Gardner, Tbhotch, The Thing That Should Not Be, The mistress11, TigerK 69, TonyTheTiger, Trebor, Vegaswikian1, WBardwin, WLRoss, WPSU, WesleyDodds, Wikiphilia, Will Beback, Woohookitty, Wrelwser43, Wwwwolf, Xenfreak, Y2kcrazyjoker4, Ylee, YoungFreud, Zoicon5, 119 anonymous edits ABO blood group system  Source: http://en.wikipedia.org/w/index.php?oldid=549278574  Contributors: 2D, 86.** IP, 9CL, A412, AManWithNoPlan, Abrahami, Aka042, Alansohn, Alextrevelian 006, Alpha2zee, Anonywiki, Apers0n, Arcadian, Ashok modhvadia, AssegaiAli, Atlantima, BQmUB2010126, Bakanov, Bedoyere, BennettL, BiT, Blix000, Blodaterpass2, Bobblehead, BonifaceFR, Booyabazooka, Capricorn42, CarrotMan, CecilWard, Ceyockey, Champlax, ChrisCork, Closedmouth, Cmglee, Cybercobra, DavidBrooks, Dcp07, Diberri, DocWatson42, Dr laura dean, Dr.saptarshi, DrMicro, Drcoghill, Droll, Drphilharmonic, Ecessny5, Espresso Addict, Ettrig, Eurobas, Favonian, Fetofs, Finlay, FlieGerFaUstMe262, Flopster2, Fredlexxa, Fsotrain09, Fumiichiro, Funandtrvl, Gadfium, Galahaad, Genie, Gigemag76, Glevum, GreenScrubs, Grunny, Guidod, Gurch, Guy Peters, Hairy Dude, Heero Kirashami, HenryLi, Hflanagan, HoraceSeaver, Ian.thomson, Imagin8or, InvictaHOG, IrfanFaiz, J04n, JQF, Jabaway, James086, Jimp, Joseolgon, Joseph Solis in Australia, Joshua Issac, Jstanley, Judicatus, Kevgermany, Kusunose, Last22, Leeyc0, Leolaursen, LittleHow, Lkfffffgf, Logan, Lygophile, MarcoTolo, Martial75, Materialscientist, Michael006, Mikael Häggström, Mike92591, MithrandirAgain, Mjbeeman, MouseVII, Moxy, MrOllie, Muntuwandi, Naraht, Neil916, NeonMerlin, Nepenthes, Niceguyedc, Nifky?, Noahspurrier, Nono64, Nutfortuna, ONEder Boy, Pauli133, Pevernagie, Phatom87, Pirulito, Prari, Primo6711, Proquence, Qwfp, R. 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Shaw, Rich Farmbrough, Richard001, Richwales, Rjwilmsi, Rlaine, Robin S, Rursus, SDY, SWAdair, Saaga, Scientizzle, Scottyaz, Sermadison, Shanes, Shawisland, Skylark42, Sl, Sligocki, Snowmanradio, Sobreira, Spellmagi, Spencer, Stevenfruitsmaak, Sun Creator, Swid, Tallan, Tcncv, Thaurisil, The Anome, The Moose, Tkonuk, Tom.carvajal, Trusilver, TylerDurden8823, Urwoqqi, Veinor, Verbivorous, Viriditas, Whoop whoop pull up, WikipedianMarlith, Willking1979, Woohookitty, Wouterstomp, Xinoph, YassineMrabet, Yt95, 222 anonymous edits Hh antigen system  Source: http://en.wikipedia.org/w/index.php?oldid=550106919  Contributors: Akriasas, Alcmaeonid, Alensha, Alpha2zee, Amatulic, Anil1956, Anthony Appleyard, Anthonyhcole, Apers0n, Arcadian, Brandon, Cronostvg, Cybercobra, DarkerFate, DavidK93, Diberri, Dietzel65, DragonflySixtyseven, Dreamyshade, Dycedarg, Filip em, Grothmag, HiEv, HunterX, Icarusgeek, InvictaHOG, Jasonid, Joshk, Kinkreet, Kissekatt, Kuebi, Leeyc0, Miss Madeline, Mmxx, Nichalp, Quendus, Ruakh, Ryancooper.blue93, Scubafish, SiobhanHansa, Sl, Snowmanradio, Spoonsfreak, Squalk25, Steven Luo, Sukhu.1313, Superm401, TBSMagill, The Anome, Thorwald, Tim1357, TinyMark, Tony Sidaway, Tsiaojian lee, Vinnypatel, Vinnyzz, Vrenator, Widr, Xetrov znt, ☂, 121 anonymous edits

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Image Sources, Licenses and Contributors File:Symbol template class.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Symbol_template_class.svg  License: Public Domain  Contributors: Anomie Image:ADN animation.gif  Source: http://en.wikipedia.org/w/index.php?title=File:ADN_animation.gif  License: Public Domain  Contributors: brian0918™ Image:Red Headed Young Man.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Red_Headed_Young_Man.jpg  License: GNU Free Documentation License  Contributors: Original uploader was Schwingy at en.wikipedia Image:Genetic code.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Genetic_code.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Madprime Image:DNA replication split.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_replication_split.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Madprime Image:PCWmice1.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:PCWmice1.jpg  License: Public Domain  Contributors: User FloNight on en.wikipedia File:Gene.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gene.png  License: Public Domain  Contributors: Courtesy: National Human Genome Research Institute File:DNA chemical structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_chemical_structure.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: User:Madprime File:Gene2-plain.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Gene2-plain.svg  License: Public Domain  Contributors: Forluvoft File:Rna-codons-protein.png  Source: http://en.wikipedia.org/w/index.php?title=File:Rna-codons-protein.png  License: Public Domain  Contributors: DBooth, Monkeybait, Opabinia regalis File:Gregor Mendel.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gregor_Mendel.png  License: Public Domain  Contributors: Common Good, Editor at Large, Kilom691, Liberal Freemason, QWerk, Savh, TimVickers, Wilfredor, 4 anonymous edits File:Punnett square mendel flowers.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Punnett_square_mendel_flowers.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Madprime File:Human genome by functions.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Human_genome_by_functions.svg  License: Creative Commons Zero  Contributors: Mikael Häggström File:Chromosome.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chromosome.svg  License: GNU Free Documentation License  Contributors: derivative work: Tryphon (talk) Chromosome-upright.png: Original version: Magnus Manske, this version with upright chromosome: User:Dietzel65 Image:Theodor boveri walter sutton.png  Source: http://en.wikipedia.org/w/index.php?title=File:Theodor_boveri_walter_sutton.png  License: Public Domain  Contributors: Walter_sutton.jpg: Unknown Theodor_Boveri.jpg: Unknown derivative work: Earthdirt (talk) File:Chromatin Structures.png  Source: http://en.wikipedia.org/w/index.php?title=File:Chromatin_Structures.png  License: GNU Free Documentation License  Contributors: Original uploader was Richard Wheeler at en.wikipedia Later version(s) were uploaded by Seans Potato Business at en.wikipedia. File:HumanChromosomesChromomycinA3.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:HumanChromosomesChromomycinA3.jpg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Steffen Dietzel File:Genes and base pairs on chromosomes.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Genes_and_base_pairs_on_chromosomes.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Friend of a friends File:PLoSBiol3.5.Fig1bNucleus46Chromosomes.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:PLoSBiol3.5.Fig1bNucleus46Chromosomes.jpg  License: Creative Commons Attribution 2.5  Contributors: Andreas Bolzer, Gregor Kreth, Irina Solovei, Daniela Koehler, Kaan Saracoglu, Christine Fauth, Stefan Müller, Roland Eils, Christoph Cremer, Michael R. 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Speicher, Thomas Cremer File:Human male karyotpe.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Human_male_karyotpe.gif  License: Public Domain  Contributors: Courtesy: National Human Genome Research Institute File:Haploid vs diploid.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Haploid_vs_diploid.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Ehamberg Image:Coquina variation3.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Coquina_variation3.jpg  License: GNU Free Documentation License  Contributors: Debivort Image:Punnett square mendel flowers.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Punnett_square_mendel_flowers.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Madprime File:Biston.betularia.7200.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Biston.betularia.7200.jpg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Kilom691, Olei File:Biston.betularia.f.carbonaria.7209.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Biston.betularia.f.carbonaria.7209.jpg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Kilom691, Olei File:Meiosis Overview.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Meiosis_Overview.svg  License: Public Domain  Contributors: National Institutes of Health file:speakerlink-new.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Speakerlink-new.svg  License: Creative Commons Zero  Contributors: User:Kelvinsong Image:gametic meiosis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gametic_meiosis.png  License: GNU Free Documentation License  Contributors: Brighterorange, Deadstar, Flappiefh, Ies, Jmarchn, Maksim Image:zygotic meiosis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Zygotic_meiosis.png  License: GNU Free Documentation License  Contributors: Deadstar, Flappiefh, Ies, Jmarchn, Liftarn, Maksim File:MitosisAndMeiosis_en.png  Source: http://en.wikipedia.org/w/index.php?title=File:MitosisAndMeiosis_en.png  License: Creative Commons Attribution-Share Alike  Contributors: Qniemiec Image:Meiosis diagram.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Meiosis_diagram.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Marek Kultys Image:Mendelian inheritance 1 2 1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Mendelian_inheritance_1_2_1.png  License: GNU Free Documentation License  Contributors: Magnus Manske Image:Mendelian inheritance.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Mendelian_inheritance.svg  License: Public domain  Contributors: Benutzer:Magnus Manske. Original uploader was Mæx at de.wikipedia Image:Dihybrid cross.png  Source: http://en.wikipedia.org/w/index.php?title=File:Dihybrid_cross.png  License: Public Domain  Contributors: Original uploader was Tocharianne at en.wikipedia Image:Punnett Square.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Punnett_Square.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Pbroks13 File:Dihybrid Cross Tree Method.png  Source: http://en.wikipedia.org/w/index.php?title=File:Dihybrid_Cross_Tree_Method.png  License: Public Domain  Contributors: Tim DeJulio File:homozygous cross tree method.png  Source: http://en.wikipedia.org/w/index.php?title=File:Homozygous_cross_tree_method.png  License: Public Domain  Contributors: Tim DeJulio Image:Autosomal dominant - en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Autosomal_dominant_-_en.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Domaina File:Co-dominance Rhododendron.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Co-dominance_Rhododendron.jpg  License: Creative Commons Attribution 2.0  Contributors: Anna reg, Ayacop, Bestiasonica, Cillas, FlickrLickr, FlickreviewR, Horcha, Kanonkas, Kevmin, MPF, Para, Uleli

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Image:Escherichia coli flagella TEM.png  Source: http://en.wikipedia.org/w/index.php?title=File:Escherichia_coli_flagella_TEM.png  License: unknown  Contributors: E. H. White, Content Provider: Peggy S. 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Albert Vallunen (User:albval) File:Distyly primula.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Distyly_primula.jpg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: berru file:Zonotrichia albicollis MN.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Zonotrichia_albicollis_MN.jpg  License: Creative Commons Attribution-Sharealike 3.0,2.5,2.0,1.0  Contributors: Cephas file:Zonotrichia albicollis CT.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Zonotrichia_albicollis_CT.jpg  License: Creative Commons Attribution-Sharealike 3.0,2.5,2.0,1.0  Contributors: Cephas Image:Chromosome X.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chromosome_X.svg  License: unknown  Contributors: Mysid Image:Sd4hi-unten-crop.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Sd4hi-unten-crop.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:Dietzel65, Steffen Dietzel Image:Chromosome X Etude Inactivation X.PNG  Source: http://en.wikipedia.org/w/index.php?title=File:Chromosome_X_Etude_Inactivation_X.PNG  License: Public Domain  Contributors: Original uploader was Mirmillon at fr.wikipedia Image:Chromosome Y.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chromosome_Y.svg  License: unknown  Contributors: Mysid file:PBB_Protein_SRY_image.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:PBB_Protein_SRY_image.jpg  License: Public Domain  Contributors: www.pdb.org file:PBB_GE_SRY_207893_at_tn.png  Source: http://en.wikipedia.org/w/index.php?title=File:PBB_GE_SRY_207893_at_tn.png  License: GNU Free Documentation License  Contributors: Image:BarrBodyBMC Biology2-21-Fig1clip293px.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:BarrBodyBMC_Biology2-21-Fig1clip293px.jpg  License: Creative Commons Attribution 2.0  Contributors: Stanley M Gartler, Kartik R Varadarajan, Ping Luo, Theresa K Canfield, Jeff Traynor, Uta Francke and R Scott Hansen

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Sheler Image:autorecessive.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Autorecessive.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: en:User:Cburnett File:Trisomy Detection in GeneMarker.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Trisomy_Detection_in_GeneMarker.jpg  License: Public Domain  Contributors: Tammyz06, 1 anonymous edits File:Translocation-4-20.png  Source: http://en.wikipedia.org/w/index.php?title=File:Translocation-4-20.png  License: Public Domain  Contributors: Courtesy: National Human Genome Research Institute File:Chromosomal translocations.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chromosomal_translocations.svg  License: Public Domain  Contributors: Mikael Häggström Image:6-year old tortoise shell cat.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:6-year_old_tortoise_shell_cat.jpg  License: Public Domain  Contributors: Michael Bodega. 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