Genetics for Pediatricians

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Derek Johnston Children’s Department, University Hospital, Queen’s Medical Centre, Nottingham, UK

“Pediatricians will find this easy-to-read book a major step forward in their clinical practice. It should be of interest to working pediatricians who need help in diagnosing syndromes and in understanding the molecular tests that are needed for diagnosis. It wisely does not attempt to discuss every single genetic condition that exists, but confines itself to the important conditions.”

Genetics for Mohnish Suri, Ian D Young

“This text is designed to be readily accessible, and effectively blends clinical features with molecular and clinical genetics. It will provide a valuable bridge between standard pediatric sources and Internet-provided databases. Suri and Young are highly respected clinical geneticists with vast experience in the pediatric applications of their speciality. They are also accomplished communicators – they recognize the challenges of clinical syndrome identification, and the necessity to balance diagnostic enthusiasm with restraint when it comes to selecting from an ever-expanding repertoire of investigations, many of which generate both personal and financial pressures.”

Genetics for Pediatricians

Genetic testing plays an important role in the investigation of almost every child who presents with one of the many common inherited disorders. It can be difficult for even the most conscientious practitioner to keep abreast of developments and to appreciate both the significance and the relevance of some of the major discoveries of recent years. So, it is with the busy general pediatrician in mind that this contemporary account of the molecular aspects of pediatric disorders has been prepared.

Series Editor Eli Hatchwell

ISBN 1-901346-63-3

Remedica

346633

Pediatricians Mohnish Suri Ian D Young

Jo Sibert Head of Department and Professor of Child Health, Department of Child Health, University of Wales School of Medicine, Cardiff, UK

9 781901

Remedica genetics series

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Genetics for Pediatricians

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The Remedica Genetics for… Series Genetics for Cardiologists Genetics for Dermatologists Genetics for Endocrinologists Genetics for Hematologists Genetics for Oncologists Genetics for Ophthalmologists Genetics for Orthopedic Surgeons Genetics for Pediatricians Genetics for Pulmonologists Genetics for Rheumatologists

Published by Remedica Publishing 32–38 Osnaburgh Street, London, NW1 3ND, UK 20 N Wacker Drive, Suite 1642, Chicago, IL 60606, USA E-mail: [email protected] www.remedica.com Publisher: Andrew Ward In-house editors: Thomas Moberly and James Griffin © 2004 Remedica Publishing While every effort is made by the publishers and authors to see that no inaccurate or misleading data, opinions, or statements appear in this book, they wish to make it clear that the material contained in the publication represents a summary of the independent evaluations and opinions of the authors and contributors. As a consequence, the authors, publishers, and any sponsoring company accept no responsibility for the consequences of any such inaccurate or misleading data, opinions, or statements. Neither do they endorse the content of the publication or the use of any drug or device in a way that lies outside its current licensed application in any territory. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher. ISBN 1 901346 63 3 ISSN 1472 4618 British Library Cataloguing-in Publication Data A catalogue record for this book is available from the British Library.

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Genetics for Pediatricians Mohnish Suri Department of Clinical Genetics City Hospital Nottingham UK Ian D Young Department of Clinical Genetics Leicester Royal Infirmary Leicester UK Series Editor Eli Hatchwell Investigator Cold Spring Harbor Laboratory USA

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To our wives and parents.

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Introduction to the Genetics for… series Medicine is changing. The revolution in molecular genetics has fundamentally altered our notions of disease etiology and classification, and promises novel therapeutic interventions. Standard diagnostic approaches to disease focused entirely on clinical features and relatively crude clinical diagnostic tests. Little account was traditionally taken of possible familial influences in disease. The rapidity of the genetics revolution has left many physicians behind, particularly those whose medical education largely preceded its birth. Even for those who might have been aware of molecular genetics and its possible impact, the field was often viewed as highly specialist and not necessarily relevant to everyday clinical practice. Furthermore, while genetic disorders were viewed as representing a small minority of the total clinical load, it is now becoming clear that the opposite is true: few clinical conditions are totally without some genetic influence. The physician will soon need to be as familiar with genetic testing as he/she is with routine hematology and biochemistry analysis. While rapid and routine testing in molecular genetics is still an evolving field, in many situations such tests are already routine and represent essential adjuncts to clinical diagnosis (a good example is cystic fibrosis). This series of monographs is intended to bring specialists up to date in molecular genetics, both generally and also in very specific ways that are relevant to the given specialty. The aims are generally two-fold: (i)

to set the relevant specialty in the context of the new genetics in general and more specifically

(ii)

to allow the specialist, with little experience of genetics or its nomenclature, an entry into the world of genetic testing as it pertains to his/her specialty

These monographs are not intended as comprehensive accounts of each specialty — such reference texts are already available. Emphasis has been placed on those disorders with a strong genetic etiology and, in particular, those for which diagnostic testing is available.

Genetics for Pediatricians

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The glossary is designed as a general introduction to molecular genetics and its language. The revolution in genetics has been paralleled in recent years by the information revolution. The two complement each other, and the World Wide Web is a rich source of information about genetics. The following sites are highly recommended as sources of information: 1.

PubMed. Free on-line database of medical literature. http://www.ncbi.nlm.nih.gov/PubMed/

2.

NCBI. Main entry to genome databases and other information about the human genome project. http://www.ncbi.nlm.nih.gov/

3.

OMIM. Online Mendelian Inheritance in Man. The Online version of McKusick’s catalogue of Mendelian disorders. Excellent links to PubMed and other databases. http://www.ncbi.nlm.nih.gov/omim/

4.

Mutation database, Cardiff. http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html

5.

National Coalition for Health Professional Education in Genetics. An organization designed to prepare health professionals for the genomics revolution. http://www.nchpeg.org/

Finally, a series of articles from the New England Journal of Medicine, entitled Genomic Medicine, has been made available free of charge at http://www.nejm.org. Eli Hatchwell Cold Spring Harbor Laboratory

Introduction

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Preface There can be very few areas of medicine in which progress has been achieved at such a rapid pace as molecular genetics. Almost every common single-gene disorder has succumbed to the march of scientific progress to the extent that genetic testing now plays an important role in the investigation of almost every child who presents with one of the many common inherited disorders which make a major contribution to pediatric morbidity and mortality throughout the world. The rate of progress is such that it can be difficult for even the most conscientious practitioner to keep abreast of developments and to appreciate both the significance and the relevance of some of the major discoveries of recent years. It is with the busy general pediatrician in mind that this contemporary account of the molecular aspects of pediatric disorders has been prepared. The number of conditions which have been mapped or in which the causative gene has been isolated is vast. Thus in order to ensure that this text is of manageable proportions, coverage has been restricted to the more common single-gene disorders which are likely to be encountered in general pediatric practice. “Small print” obscurities and the many inborn errors for which comprehensive biochemical testing is available have generally been omitted. Instead attention has been focused on the more common conditions in which molecular analysis can play an important role in diagnosis or in the management of a child and his or her family. In some instances, notably with eye and skin disorders, we have also omitted rare disorders which fall within the remit of other specialties, particularly when these have received detailed coverage in other books in this series. In addition to providing a unique insight into the cause of so many previously unexplained disorders, recent advances in molecular genetics have also demonstrated that, far from being straightforward, Mendelian inheritance and its contribution to genetic disease can be remarkably complex. Thus a “simple” disorder such as cystic fibrosis has proved to be extremely heterogeneous both clinically and at the molecular level, with over 1,000 different mutations reported at the main disease locus. Indeed, for many conditions such as cystic fibrosis and β-thalassemia, mutational heterogeneity has proved to be the norm. Entities such as nonsyndromal sensorineural hearing loss illustrate Genetics for Pediatricians

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that locus heterogeneity can also be extremely important. Further examples of etiologic complexity are provided by the Bardet–Biedl syndrome, which shows not only locus heterogeneity but also the curious phenomenon of triallelic inheritance, and by Hirschsprung disease, for which the concept of synergistic heterozygosity has started to shed light on how genes at several loci can interact to contribute to what is commonly referred to as oligogenic or polygenic inheritance. And if this was not enough, research on pediatric disorders such as the fragile X syndrome and the Angelman/Prader–Willi syndromes has identified “new” genetic mechanisms such as triplet repeat instability with anticipation, and imprinting/uniparental disomy, respectively. So as well as providing a useful up-to-date account of molecular pathogenesis, we hope that this text will also help readers become better acquainted with some of the new and exciting developments that have characterized molecular genetic research over the last few years. In writing this book we would like to offer our thanks to colleagues who have provided photographs, and to Mrs Diane Castledine for secretarial assistance. Above all we would like to express our gratitude to, and admiration for, the many children and families who, over the years, have taught us so much more than they could possibly have learned from us. Mohnish Suri Ian D Young

Preface

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Contents 1. Progressive Ataxias and Neurologic Disorders Ataxia–Telangiectasia Duchenne Muscular Dystrophy Facioscapulohumeral Muscular Dystrophy Friedreich Ataxia Hereditary Motor and Sensory Neuropathy Limb-girdle Muscular Dystrophy Myotonic Dystrophy Spinal Muscular Atrophy

1 2 4 7 8 10 18 23 27

2. Cerebral Malformations and Mental Retardation Syndromes Angelman Syndrome Fragile X Syndrome Holoprosencephaly Hunter Syndrome Huntington Disease Lesch–Nyhan Syndrome Lissencephaly Lowe Syndrome Neuronal Ceroid Lipofuscinosis Pelizaeus–Merzbacher Syndrome Prader–Willi Syndrome Rett Syndrome X-linked Adrenoleukodystrophy X-linked α-Thalassemia and Mental Retardation Syndrome X-linked Hydrocephalus

29 30 34 36 40 41 43 45 52 53 57 59 61 62 64 66

3. Disorders of Vision

69 70 72 74 75 79 80

Aniridia Bardet–Biedl Syndrome Juvenile Retinoschisis Leber Congenital Amaurosis Norrie Disease Rieger Syndrome

Genetics for Pediatricians

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4. Hearing Disorders Nonsyndromal Hearing Loss Hearing Loss due to Connexin 26 Gene Defect Pendred Syndrome Usher Syndrome Waardenburg Syndrome

83 84 85 86 87 90

5. Neurocutaneous Disorders and Childhood Cancer Multiple Endocrine Neoplasia Type 2 Neurofibromatosis Type 1 Retinoblastoma Tuberous Sclerosis von Hippel–Lindau Disease

93 94 96 98 101 103

6. Connective Tissue and Skeletal Disorders Achondroplasia Ehlers–Danlos Syndrome Hereditary Multiple Exostoses Marfan Syndrome Osteogenesis Imperfecta Pseudoachondroplasia Stickler Syndrome

107 108 110 115 117 119 124 125

7. Cardio-respiratory Disorders Barth Syndrome Cystic Fibrosis DiGeorge/Shprintzen Syndrome Holt–Oram Syndrome Laterality Defects Noonan Syndrome Primary Ciliary Dyskinesia Williams Syndrome

129 130 131 133 135 137 138 139 141

Contents

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8. Craniofacial Disorders Apert Syndrome Crouzon Syndrome Greig Syndrome Pfeiffer Syndrome Rubinstein–Taybi Syndrome Saethre–Chotzen Syndrome Sotos Syndrome Treacher Collins Syndrome Van der Woude Syndrome

143 144 146 148 149 151 152 153 154 155

9. Endocrine Disorders Androgen Insensitivity Syndrome Congenital Adrenal Hyperplasia Diabetes Insipidus Growth Hormone Deficiency Growth Hormone Receptor Defects Panhypopituitarism Pseudohypoparathyroidism

157 158 160 163 164 166 167 169

10. Gastrointestinal and Hepatic Diseases Alagille Syndrome α1-Antitrypsin Deficiency Hirschsprung Disease

173 174 175 177

11. Hematologic Disorders Fanconi Anemia Glucose-6-Phosphate Dehydrogenase Deficiency Hemophilia A Hemophilia B Hereditary Elliptocytosis Hereditary Spherocytosis Sickle Cell Anemia α-Thalassemia β-Thalassemia von Willebrand Disease

181 182 183 185 187 189 190 193 194 197 198

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12. Immunologic Disorders Bruton Agammaglobulinemia Chronic Granulomatous Disease Severe Combined Immunodeficiency Wiskott–Aldrich Syndrome

201 202 203 205 207

13. Metabolic Disorders Medium Chain Acyl-CoA Dehydrogenase Deficiency Menkes Disease Ornithine Transcarbamylase Deficiency Phenylketonuria Wilson Disease

209 210 211 212 214 215

14. Renal Disorders

217 218 220 224 225 226

Alport Syndrome Beckwith–Wiedemann Syndrome Cystinosis Orofaciodigital Syndrome Type I Polycystic Kidney Disease 15. Abbreviations

229

16. Glossary

235

17. Index

285

Contents

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1 1. Progressive Ataxias and Neurologic Disorders

Ataxia–Telangiectasia 2 Duchenne Muscular Dystrophy 4 Facioscapulohumeral Muscular Dystrophy 7 Friedreich Ataxia 8 Hereditary Motor and Sensory Neuropathy 10 Limb-girdle Muscular Dystrophy 18 Myotonic Dystrophy 23 Spinal Muscular Atrophy 27

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Ataxia–Telangiectasia (also known as: AT; Louis-Bar syndrome) MIM

208900

Clinical features

AT is a neurocutaneous syndrome. Patients present with progressive truncal and gait ataxia, unusual head movements, choreoathetosis, and oculomotor apraxia in both horizontal and vertical gaze. Other features include motor developmental delay, dysarthria, and mask-like facies. Telangiectasia appears over the bulbar conjunctiva, face, and ears from the age of 3–4 years (see Figure 1). Many children have a history of recurrent respiratory infections, and 30%–40% of patients develop a malignancy. These include T-cell leukemias and B-cell lymphomas in children and epithelial tumors (such as breast and ovarian cancer) in adults. Patients with AT usually survive into their twenties, although longer survival periods have been documented. Investigations show elevated levels of α-fetoprotein and carcinoembryonic antigen and reduced levels of immunoglobulin (Ig)G2, IgA, and IgE. Chromosome analysis can show reciprocal balanced translocations involving the short arm of chromosome 7 and the long arm of chromosome 14, or the short arm of chromosome 2 and the long arm of chromosome 22.

Age of onset

Most children present with ataxia between the ages of 1 and 3 years.

Epidemiology

The population incidence is estimated to be about 1 in 40,000 to 1 in 100,000 live births. About 1% of the general population are believed to be carriers (heterozygotes).

Inheritance

Autosomal recessive

Chromosomal location

11q22.3

Gene

ATM (ataxia–telangiectasia mutated)

Mutational spectrum

Over 400 mutations have been described. These include small and large deletions and insertions, as well as nonsense, missense, and splice-site mutations. About 65%–70% of mutations result in protein truncation, and these mutations produce no detectable protein. The remaining

2

Ataxia–Telangiectasia

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Figure 1. Telangiectasia over the bulbar conjunctiva in a child with ataxia–telangiectasia.

mutations result in the production of a normal-sized protein that is nonfunctional. Almost all nonconsanguineous patients are compound heterozygotes, ie, they have different mutations in their two ATM alleles. Molecular pathogenesis

ATM has 66 exons and encodes a protein with 3,056 amino acids. The ATM protein is ubiquitously expressed and has homology to yeast and mammalian phosphatidylinositol-3 kinases, which are involved in signal transduction, cell cycle control, and DNA repair. It is believed that the ATM protein phosphorylates several other proteins, including p53, ABL, BRCA1, TERF1, RAD9, and nibrin (the protein product of the gene for Nijmegen breakage syndrome, MIM 251260), after cell exposure to ionizing radiation. This delays the progression of the cell through the cell cycle at the G1/S checkpoint, allowing the cell to repair DNA damage before entering the S phase. Without ATM protein the cell would be able to progress to the S phase without repairing the DNA damage sustained by radiation exposure, which could predispose to the development of cancer. The molecular pathogenesis of the neurocutaneous phenotype of AT is unknown.

Genetic diagnosis and counseling

The diagnosis can be confirmed by demonstrating increased chromosomal breakage in cultured lymphocytes after X-irradiation and reduced or absent expression of ATM protein in lymphocytes. Genetic testing is only available on a research basis.

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Counseling is on the basis of autosomal recessive inheritance. Carrier females (particularly those who carry a missense mutation) are at increased risk of developing breast cancer. Missense mutations in ATM are believed to be associated with an increased cancer risk as a result of a dominant-negative effect. Prenatal diagnosis is possible by linkage analysis or by ATM mutation analysis if mutations have been identified previously in an affected child from the family. Prenatal diagnosis has been attempted by amniocentesis followed by X-irradiation of cultured amniocytes to look for chromosomal breakage, but this method of prenatal diagnosis is unreliable.

Duchenne Muscular Dystrophy (also known as: DMD) MIM

310200

Clinical features

This condition mainly affects males, who present with delayed motor-developmental milestones, proximal muscle weakness with pseudohypertrophy of some muscles, particularly the calves (see Figure 2), and cardiomyopathy. The muscle weakness is progressive. In classical cases, loss of ambulation occurs before the age of 12 years and death occurs in the twenties. Intermediate forms of DMD exist in which progression is slower, with loss of ambulation occurring between 11 and 16 years of age. Learning difficulties are seen in approximately 60% of patients. Death is usually due to respiratory infection or cardiomyopathy. About 2.5% of female carriers are symptomatic (manifesting carriers).

Figure 2. Calf hypertrophy in a boy with Duchenne muscular dystrophy.

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Duchenne Muscular Dystrophy

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Age of onset

Usually in the first year of life, although diagnosis is often delayed.

Epidemiology

This is the most common form of muscular dystrophy, affecting 1 in 3,500 live-born males. The prevalence of symptomatic carriers in the female population is estimated to be 1 in 100,000.

Inheritance

X-linked recessive

Chromosomal location

Xp21.2

Gene

DMD (dystrophin)

Mutational spectrum

An intragenic deletion that involves one or more exons is present in 65%–70% of patients. There are two deletion hotspots, one between exons 2 and 20 and the other between exons 44 and 53. Intragenic duplications are seen in 5%–6% of cases. The remainder of cases involve point mutations (nonsense, missense, and splice-site mutations), which are distributed across the whole gene.

Molecular pathogenesis

DMD is the largest known gene in the human genome. It is 2.4 Mb in size and composed of 79 exons. It encodes a large, rod-shaped cytoskeletal protein made up of 3,685 amino acids. The dystrophin protein has an actin-binding domain, two calpain-homology domains, 22 spectrin repeats, one WW domain (a short domain of about 40 amino acids that contains two tryptophan residues that are spaced 20–23 amino acids apart – the term WW derives from the two tryptophan residues, as the single letter code for tryptophan is W) and one ZZ-type zinc finger domain. The gene is subject to alternative splicing, and there are at least four isoforms of dystrophin. These include a muscle (M) isoform, a brain (B) isoform, and a cerebellar Purkinje (CP) isoform. Dystrophin is expressed in several tissues and plays an important role in anchoring the cytoskeleton to the plasma membrane. In muscle, dystrophin links the sarcolemmal cytoskeleton to the extracellular matrix. It is thought to protect the sarcolemma during muscular contractions. Mutations that result in the DMD phenotype are associated with protein truncation or loss of the translational reading frame. These mutations result in the absence of dystrophin. Mutations that maintain the translational reading frame result in the phenotype of Becker muscular dystrophy (MIM 300376). These

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mutations result in the production of a shortened and only partially functional protein. Patients with Becker muscular dystrophy have clinical features similar to those of DMD, but the condition is milder, progression is slower, and survival is prolonged. Mutations in the 5´ end of DMD and in-frame deletions in exons 48 and 49 can also cause X-linked dilated cardiomyopathy (MIM 302045). Mutations in the 5´ end of DMD result in failure to transcribe the M isoform in skeletal and cardiac muscle. However, the absence of this isoform in skeletal muscle can be compensated for by up-regulation of the B and CP isoforms. This does not appear to be the case in cardiac muscle, where the lack of dystrophin expression results in cardiomyopathy. The mechanism by which in-frame deletions in exons 48 and 49 cause X-linked dilated cardiomyopathy is not understood, but it has been suggested that intron 48 might contain sequences that are necessary for the expression of dystrophin in cardiac muscle. Genetic diagnosis and counseling

The diagnosis of DMD is based on clinical features, markedly elevated plasma creatine kinase (CK) levels, muscle biopsy (with immunohistochemistry using monoclonal antibodies to dystrophin), and mutation testing. Routine genetic testing can only detect intragenic deletions and duplications. Testing for point mutations in DMD is only undertaken in a few specialized research laboratories and is best performed on dystrophin mRNA extracted from a fresh or frozen muscle biopsy. Genetic counseling is on an X-linked recessive basis. Female relatives of affected males who have an intragenic deletion or duplication can be offered carrier testing. Carrier females have a 50% chance of having an affected son, and can be offered a reliable genetic prenatal test for this condition by chorionic villus sampling. There is a two-thirds chance that the mother of a sporadic case (single affected male with no family history) is a carrier. The mother of a sporadic case can also have somatic or gonadal mosaicism for the DMD mutation. Therefore, there is a 10%–15% recurrence risk of DMD in a subsequent pregnancy for the mother of a sporadic case. In DMD families in which the DMD mutation cannot be identified, carrier testing involves linkage analysis and serial plasma CK assays. Linkage analysis using intragenic and flanking markers can also be used for prenatal diagnosis in these families.

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Duchenne Muscular Dystrophy

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Facioscapulohumeral Muscular Dystrophy (also known as: FSHMD) MIM

158900 (type 1A) 158901 (type 1B)

Clinical features

This is a slowly progressive muscular dystrophy. The affected patient usually presents with facial weakness, shoulder-girdle weakness and wasting, and scapular winging. Later, there is involvement of feet and hip-girdle dorsiflexors. There is often striking wasting of the neck muscles and the muscles of the upper arm. Retinal vasculopathy and high-frequency sensorineural hearing loss are also recognized features.

Age of onset

Late childhood or adolescence.

Epidemiology

The incidence of FSHMD is approximately 1 in 20,000.

Inheritance

Autosomal dominant

Chromosomal location

Type 1A: 4q35 Type 1B: unknown

Gene

Unknown (both types)

Mutational spectrum

Most cases of FSHMD are type 1A. Although the gene for this condition has not yet been identified, almost all patients have a chromosomal rearrangement in the subtelomeric region of the long arm of chromosome 4 (4q35). This region contains a polymorphic 3.3-kb repeat element termed D4Z4. In the general population, the number of D4Z4 repeats varies from 10 to more than 100. Affected individuals have a deletion in this region that reduces the number of D4Z4 repeats to less than 10. This reduction is the basis of a diagnostic molecular genetic test for FSHMD type 1A.

Molecular pathogenesis

Unknown. It has been suggested that deletion of the D4Z4 repeat sequences could interfere with the expression of a gene located some distance away on the long arm of chromosome 4 by a “position effect”. Recent work suggests that an element within the D4Z4 repeat sequence specifically binds a multiprotein complex that mediates transcriptional repression of genes at 4q35. Deletion of D4Z4 sequences below a certain number could result in a reduction in the number of repressor complexes.

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This could decrease or abolish the transcriptional repression of 4q35 genes, with overexpression of one or more of these genes resulting in the FSHMD phenotype. Genetic diagnosis and counseling

Genetic testing is routinely available and enables a diagnosis to be made in most cases. Counseling is on the basis of autosomal dominant inheritance. About 30% of patients represent new mutations. The condition demonstrates 95% penetrance by the age of 20 years, although penetrance is lower in females. Anticipation has been described in some families. Prenatal testing can be done by genetic testing or, in suitable families, by linkage analysis.

Friedreich Ataxia MIM

229300 (Friedreich ataxia 1) 601992 (Friedreich ataxia 2)

Clinical features

This is the most common cause of cerebellar ataxia in childhood. Affected children present with dysarthria and progressive ataxia of their gait. Neurologic examination demonstrates weakness of the lower limbs, absent knee and ankle jerks, extensor plantar reflexes, decreased position and vibration sense in legs, positive Romberg sign, and pes cavus. Other features include scoliosis, diabetes mellitus, optic atrophy, and deafness. Nerve conduction studies show reduced or absent sensory action potentials, but normal motor-nerve conduction velocities. Echocardiograms show features of hypertrophic cardiomyopathy in 70% of patients.

Age of onset

Usually between 5 and 15 years of age. Almost all cases present before the age of 25 years, although onset after this age has also been described (late-onset form).

Epidemiology

The estimated population prevalence is 1–2 per 50,000. The carrier (heterozygote) frequency is between 1 in 60 and 1 in 110.

Inheritance

Autosomal recessive

Chromosomal location

Friedreich ataxia 1: 9q13 Friedreich ataxia 2: 9p11–p23

8

Friedreich Ataxia

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Gene

Friedreich ataxia 1: FRDA (frataxin) Friedreich ataxia 2: unknown

Mutational spectrum

FRDA has seven exons that are subject to alternative splicing. The major protein product of this gene is the 210-amino-acid protein frataxin. This is encoded by exons 1–4 spliced to exon 5A. The majority of patients (~96%) are homozygous for an expansion of a GAA triplet repeat motif in the first intron of the gene. The normal number of GAA triplet repeats is 9–22. In affected individuals the size range is 66–1,700 repeats, with most patients having 600–1,200 repeats. The remaining patients are compound heterozygotes for a pathogenic GAA repeat expansion in one FRDA allele and an inactivating mutation (nonsense or frame-shift) in the other allele.

Molecular pathogenesis

Frataxin is located in the inner mitochondrial membrane, where it plays an important role in oxidative phosphorylation and iron homeostasis. The GAA repeat expansion interferes with the transcription of FRDA, resulting in frataxin deficiency. This is associated with a defect of mitochondrial oxidative phosphorylation and accumulation of iron within the mitochondria. Thus, Friedreich ataxia is essentially a mitochondrial disorder and this is reflected in its clinical features.

Genetic diagnosis and counseling

Genetic testing is available from diagnostic laboratories. However, it is limited to testing for the pathogenic GAA repeat expansion. Counseling is on the basis of autosomal recessive inheritance. The sibling recurrence risk is 25%, but there can be marked variability in the expression of the condition in members of the same family. This can manifest as a different age of onset and/or a difference in the rate of progression. Carrier testing and prenatal diagnosis are available in families where molecular genetic analysis has confirmed that the affected individual is homozygous for a GAA repeat expansion.

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Hereditary Motor and Sensory Neuropathy (also known as: HMSN; Charcot–Marie–Tooth disease; peroneal muscular atrophy) The hereditary motor and sensory neuropathies are a clinically and genetically heterogeneous group of disorders. Four main clinical phenotypes can be recognized: classical HMSN, Dejerine–Sottas syndrome, congenital hypomyelinating neuropathy (CHN), and hereditary neuropathy with liability to pressure palsies (HNPP). Each of these phenotypes is discussed in turn. Table 1 summarizes the classification, distinguishing clinical features, inheritance patterns, and molecular genetics of the various forms of HMSN. MIM

See Table 1.

Clinical Features

Classical HMSN/HMSN I & II Patients with classical HMSN present with distal weakness and wasting of the legs, often associated with pes cavus and loss of ankle jerks. Sensory symptoms are usually mild and include paresthesia of the hands and feet. The condition progresses at a variable rate to involve the small muscles of the hands and proximal parts of the lower limbs. Classical HMSN patients can be divided into two groups based on their nerve conduction velocities (NCVs). Patients with HMSN I have a demyelinating neuropathy with reduced NCVs (patients over the age of 2 years have a motor NCV of 38 m/s in the median nerve). Dejerine–Sottas syndrome/HMSN III The Dejerine–Sottas syndrome phenotype is more severe than that of classical HMSN, and patients with this condition present with hypotonia, generalized muscle weakness, motor developmental delay, ataxia, and areflexia. They often have palpable peripheral nerves. Muscle weakness tends to progress more rapidly than in classical HMSN, and patients are often nonambulatory by adolescence. However, the condition is quite variable in its severity and progression. Nerve conduction studies show very low NCVs (often 300

AD

164500

Spinocerebellar ataxia type 8 (SCA8)

SCA8 13q21

CTG

3’UTR

6–37

–

~107–2501

AD

603680

Spinocerebellar ataxia type 10 (SCA10)

SCA10 22q13-qter

ATTCT

intron 9

10–22

–

500–4,500

AD

603516

Spinocerebellar ataxia type 12 (SCA12)

PP2R2B 5q31-33

CAG

5’UTR

7–28

–

66–78

AD

604326

Myotonic dystrophy (DM)

DMPK 19q13.3

CTG

3’UTR

5–37

~50–180

~200–>2,000

AD

160900

Table 1. “Classical” repeat expansion disorders. 1Longer alleles exist but are not associated with disease. AD: autosomal dominant; AR: autosomal recessive; ORF: open reading frame (coding region); 3´ UTR: 3´ untranslated region (downstream of gene); 5´ UTR: 5´ untranslated region (upstream of gene); XLR: X-linked recessive.

Empirical Based on observation, rather than detailed knowledge of, eg, modes recurrence of inheritance or environmental factors. risk – recurrence risk Endonuclease

An enzyme that cleaves DNA at an internal site (see also restriction enzyme).

Euchromatin

Chromatin that stains lightly with trypsin G banding and contains active/potentially active genes.

Euploidy

Having a normal chromosome complement.

Glossary

249

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Exon

Coding part of a gene. Historically, it was believed that all of a DNA sequence is mirrored exactly on the messenger RNA (mRNA) molecule (except for the presence of uracil in mRNA compared to thymine in DNA). It was a surprise to discover that this is generally not the case. The genomic sequence of a gene has two components: exons and introns. The exons are found in both the genomic sequence and the mRNA, whereas the introns are found only in the genomic sequence. The mRNA for dystrophin, an X-linked gene associated with Duchenne muscular dystrophy (DMD), is 14,000 base pairs long but the genomic sequence is spread over a distance of 1.5 million base pairs, because of the presence of very long intronic sequences. After the genomic sequence is initially transcribed to RNA, a complex system ensures specific removal of introns. This system is known as splicing.

Expressivity

Degree of expression of a disease. In some disorders, individuals carrying the same mutation may manifest wide variability in severity of the disorder. Autosomal dominant disorders are often associated with variable expressivity, a good example being Marfan’s syndrome. Variable expressivity is to be differentiated from incomplete penetrance, an all or none phenomenon that refers to the complete absence of a phenotype in some obligate carriers.

F Familial

Any trait that has a higher frequency in relatives of an affected individual than the general population.

FISH

Fluorescence in situ hybridization (see In situ hybridization).

Founder effect

The high frequency of a mutant allele in a population as a result of its presence in a founder (ancestor). Founder effects are particularly noticeable in relative genetic isolates, such as the Finnish or Amish.

Frame-shift mutation

Deletion/insertion of a DNA sequence that is not an exact multiple of 3 base pairs. The result is an alteration of the reading frame of the gene such that all sequence that lies beyond the mutation is missence (ie, codes for the wrong amino acids) (see Figure 8). A premature stop codon is usually encountered shortly after the frame shift.

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A

PITX2 sequence

Mutant (protein)

ATG Met

TTT Phe

TCC Ser

CCC Pro

ACC Thr

CAA Gln

Normal (protein)

ATG Met

TTT Phe

TCC Ser

CCA Pro

CCC Pro

AAC Asn

Figure 8. Frame-shift mutation. This example shows a sequence of PITX2 in a patient with Rieger’s syndrome, an autosomal dominant condition. The sequence graph shows only the abnormal sequence. The arrow indicates the insertion of a single cytosine (C) residue. When translated, the triplet code is now out of frame by 1 base pair. This totally alters the translated protein’s amino acid sequence. This leads to a premature stop codon later in the protein and results in Rieger’s syndrome.

G Gamete (germ cell)

The mature male or female reproductive cells, which contain a haploid set of chromosomes.

Gene

An ordered, specific sequence of nucleotides that controls the transmission and expression of one or more traits by specifying the sequence and structure of a particular protein or RNA molecule. Mendel defined a gene as the basic physical and functional unit of all heredity.

Gene expression

The process of converting a gene’s coded information into the existing, operating structures in the cell.

Gene mapping

Determines the relative positions of genes on a DNA molecule and plots the genetic distance in linkage units (centiMorgans) or physical distance (base pairs) between them.

Genetic code

Relationship between the sequence of bases in a nucleic acid and the order of amino acids in the polypeptide synthesized from it

Glossary

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2nd

2nd

2nd

T

C

A

G

TTT Phe [F]

TCT Ser [S]

TAT Tyr [Y]

TGT Cys [C]

T

TTC Phe [F]

TCC Ser [S]

TAC Tyr [Y]

TGC Cys [C]

C

TTA Leu [L]

TCA Ser [S]

TAA Ter [end]

TGA Ter [end]

A

TTG Leu [L]

TCG Ser [S]

TAG Ter [end]

TGG Trp [W]

G

CTT Leu [L]

CCT Pro [P]

CAT His [H]

CGT Arg [R]

T

CTC Leu [L]

CCC Pro [P]

CAC His [H]

CGC Arg [R]

C

CTA Leu [L]

CCA Pro [P]

CAA Gln [Q]

CGA Arg [R]

A

CTG Leu [L]

CCG Pro [P]

CAG Gln [Q]

CGG Arg [R]

G

ATT Ile [I]

ACT Thr [T]

AAT Asn [N]

AGT Ser [S]

T

ATC Ile [I]

ACC Thr [T]

AAC Asn [N]

AGC Ser [S]

C A

ATA Ile [I]

ACA Thr [T]

AAA Lys [K]

AGA Arg [R]

ATG Met [M]

ACG Thr [T]

AAG Lys [K]

AGG Arg [R]

G

GTT Val [V]

GCT Ala [A]

GAT Asp [D]

GGT Gly [G]

T

GTC Val [V]

GCC Ala [A]

GAC Asp [D]

GGC Gly [G]

C

GTA Val [V]

GCA Ala [A]

GAA Glu [E]

GGA Gly [G]

A

GTG Val [V]

GCG Ala [A]

GAG Glu [E]

GGG Gly [G]

G

3rd

3rd

3rd

3rd

Table 2. The genetic code. To locate a particular codon (eg, TAG, marked in bold) locate the first base (T) in the left hand column, then the second base (A) by looking at the top row, and finally the third (G) in the right hand column (TAG is a stop codon). Note the redundancy of the genetic code – for example, three different codons specify a stop signal, and threonine (Thr) is specified by any of ACT, ACC, ACA, and ACG.

(see Table 2). A sequence of three nucleic acid bases (a triplet) acts as a codeword (codon) for one amino acid or instruction (start/stop). Genetic counseling

Information/advice given to families with, or at risk of, genetic disease. Genetic counseling is a complex discipline that requires accurate diagnostic approaches, up-to-date knowledge of the genetics of the condition, an insight into the beliefs/anxieties/wishes of the individual seeking advice, intelligent risk estimation, and, above all, skill in communicating relevant information to individuals from a wide variety of educational backgrounds. Genetic counseling is most often carried out by trained medical geneticists or, in some countries, specialist genetic counselors or nurses.

Genetic heterogeneity Association of a specific phenotype with mutations at different loci. The broader the phenotypic criteria, the greater the heterogeneity (eg, mental retardation). However, even very specific phenotypes may be genetically heterogeneous. Isolated central hypothyroidism is a good example: this autosomal recessive condition is now known to be associated (in different individuals) with mutations in the TSH β 252

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chain at 1p13, the TRH receptor at 8q23, or TRH itself at 3q13.3–q21. There is no obvious distinction between the clinical phenotypes associated with these two genes. Genetic heterogeneity should not be confused with allelic heterogeneity, which refers to the presence of different mutations at the same locus. Genetic locus

A specific location on a chromosome.

Genetic map

A map of genetic landmarks deduced from linkage (recombination) analysis. Aims to determine the linear order of a set of genetic markers along a chromosome. Genetic maps differ significantly from physical maps, in that recombination frequencies are not identical across different genomic regions, resulting occasionally in large discrepancies.

Genetic marker

A gene that has an easily identifiable phenotype so that one can distinguish between those cells or individuals that do or do not have the gene. Such a gene can also be used as a probe to mark cell nuclei or chromosomes, so that they can be isolated easily or identified from other nuclei or chromosomes later.

Genetic screening

Population analysis designed to ascertain individuals at risk of either suffering or transmitting a genetic disease.

Genetically lethal

Preventing reproduction of the individual, either by causing death prior to reproductive age, or as a result of social factors making it highly unlikely (although not impossible) that the individual concerned will reproduce.

Genome

The complete DNA sequence of an individual, including the sex chromosomes and mitochondrial DNA (mtDNA). The genome of humans is estimated to have a complexity of 3.3 x 109 base pairs (per haploid genome).

Genomic

Pertaining to the genome. Genomic DNA differs from complementary DNA (cDNA) in that it contains noncoding as well as coding DNA.

Genotype

Genetic constitution of an individual, distinct from expressed features (phenotype).

Germ line

Germ cells (those cells that produce haploid gametes) and the cells from which they arise. The germ line is formed very early in embryonic development. Germ line mutations are those present constitutionally

Glossary

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in an individual (ie, in all cells of the body) as opposed to somatic mutations, which affect only a proportion of cells. Giemsa banding

Light/dark bar code obtained by staining chromosomes with Giemsa stain. Results in a unique bar code for each chromosome.

Guanine (G)

One of the bases making up DNA and RNA (pairs with cytosine).

H Haploid

The chromosome number of a normal gamete, containing one each of every individual chromosome (23 in humans).

Haploinsufficiency

The presence of one active copy of a gene/region is insufficient to compensate for the absence of the other copy. Most genes are not “haploinsufficient” – 50% reduction of gene activity does not lead to an abnormal phenotype. However, for some genes, most often those involved in early development, reduction to 50% often correlates with an abnormal phenotype. Haploinsufficiency is an important component of most contiguous gene disorders (eg, in Williams’ syndrome, heterozygous deletion of a number of genes results in the mutant phenotype, despite the presence of normal copies of all affected genes).

Hemizygous

Having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on the sex chromosomes, as they possess only one X chromosome and one Y chromosome (the exceptions being those genes with counterparts on both sex chromosomes). Deletions on autosomes produce hemizygosity in both males and females.

Heterochromatin

Contains few active genes, but is rich in highly repeated simple sequence DNA, sometimes known as satellite DNA. Heterochromatin refers to inactive regions of the genome, as opposed to euchromatin, which refers to active, gene expressing regions. Heterochromatin stains darkly with Giemsa.

Heterozygous

Presence of two different alleles at a given locus.

Histones

Simple proteins bound to DNA in chromosomes. They help to maintain chromatin structure and play an important role in regulating gene expression.

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Holandric

Pattern of inheritance displayed by mutations in genes located only on the Y chromosome. Such mutations are transmitted only from father to son.

Homologue or homologous gene

Two or more genes whose sequences manifest significant similarity because of a close evolutionary relationship. May be between species (orthologues) or within a species (paralogues).

Homologous chromosomes

Chromosomes that pair during meiosis. These chromosomes contain the same linear gene sequences as one another and derive from one parent.

Homology

Similarity in DNA or protein sequences between individuals of the same species or among different species.

Homozygous

Presence of identical alleles at a given locus.

Human gene therapy The study of approaches to treatment of human genetic disease, using the methods of modern molecular genetics. Many trials are under way studying a variety of disorders, including cystic fibrosis. Some disorders are likely to be more treatable than others – it is probably going to be easier to replace defective or absent gene sequences rather than deal with genes whose aberrant expression results in an actively toxic effect. Human genome project

Worldwide collaboration aimed at obtaining a complete sequence of the human genome. Most sequencing has been carried out in the USA, although the Sanger Centre in Cambridge, UK has sequenced one third of the genome, and centers in Japan and Europe have also contributed significantly. The first draft of the human genome was released in the summer of 2000 to much acclaim. Celera, a privately funded venture, headed by Dr Craig Ventner, also published its first draft at the same time.

Hybridization

Pairing of complementary strands of nucleic acid. Also known as re-annealing. May refer to re-annealing of DNA in solution, on a membrane (Southern blotting) or on a DNA microarray. May also be used to refer to fusion of two somatic cells, resulting in a hybrid that contains genetic information from both donors.

Glossary

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I Imprinting

A general term used to describe the phenomenon whereby a DNA sequence (coding or otherwise) carries a signal or imprint that indicates its parent of origin. For most DNA sequences, no distinction can be made between those arising paternally and those arising maternally (apart from subtle sequence variations); for imprinted sequences this is not the case. The mechanistic basis of imprinting is almost always methylation – for certain genes, the copy that has been inherited from the father is methylated, while the maternal copy is not. The situation may be reversed for other imprinted genes. Note that imprinting of a gene refers to the general phenomenon, not which parental copy is methylated (and, therefore, usually inactive). Thus, formally speaking, it is incorrect to say that a gene undergoes paternal imprinting. It is correct to say that the gene undergoes imprinting and that the inactive (methylated) copy is always the paternal one. However, in common genetics parlance, paternal imprinting is usually understood to mean the same thing.

In situ hybridization Annealing of DNA sequences to immobilized chromosomes/cells/ (ISH) tissues. Historically done using radioactively labeled probes, this is currently most often performed with fluorescently tagged molecules (fluorescent in situ hybridization – FISH, see Figure 9). ISH/FISH allows for the rapid detection of a DNA sequence within the genome. Incomplete penetrance

Complete absence of expression of the abnormal phenotype in a proportion of individuals known to be obligate carriers. To be distinguished from variable expressivity, in which the phenotype always manifests in obligate carriers, but with widely varying degrees of severity.

Index case – proband The individual through which a family medically comes to light. For example, the index case may be a baby with Down’s syndrome. Can be termed propositus (if male) or proposita (if female). Insertion

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Interruption of a chromosomal sequence as a result of insertion of material from elsewhere in the genome (either a different chromosome, or elsewhere from the same chromosome). Such insertions may result in abnormal phenotypes either because of direct interruption of a gene (uncommon), or because of the resulting imbalance (ie, increased dosage) when the chromosomes that contain the normal counterparts of the inserted sequence are also present. Genetics for Pediatricians

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Figure 9. Fluorescence in situ hybridization. FISH analysis of a patient with a complex syndrome, using a clone containing DNA from the region 8q24.3. In addition to that clone, a control from 8pter was used. The 8pter clone has yielded a signal on both homologues of chromosome 8, while the “test” clone from 8q24.3 has yielded a signal on only one homologue, demonstrating a (heterozygous) deletion in that region.

Intron

A noncoding DNA sequence that “interrupts” the protein-coding sequences of a gene; intron sequences are transcribed into messenger RNA (mRNA), but are cut out before the mRNA is translated into a protein (this process is known as splicing). Introns may contain sequences involved in regulating expression of a gene. Unlike the exon, the intron is the nucleotide sequence in a gene that is not represented in the amino acid sequence of the final gene product.

Inversion

A structural abnormality of a chromosome in which a segment is reversed, as compared to the normal orientation of the segment. An inversion may result in the reversal of a segment that lies entirely on one chromosome arm (paracentric) or one that spans (ie, contains) the centromere (pericentric). While individuals who possess an inversion are likely to be genetically balanced (and therefore usually phenotypically normal), they are at increased risk of producing unbalanced offspring because of problems at meiosis with pairing of the inversion chromosome with its normal homologue. Both deletions and duplications may result, with concomitant congenital abnormalities related to genomic imbalance, or miscarriage if the imbalance is lethal.

Glossary

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K Karyotype

A photomicrograph of an individual’s chromosomes arranged in a standard format showing the number, size, and shape of each chromosome type, and any abnormalities of chromosome number or morphology (see Figure 10).

Kilobase (kb)

1000 base pairs of DNA.

Knudson hypothesis See tumor suppressor gene

L Linkage

Coinheritance of DNA sequences/phenotypes as a result of physical proximity on a chromosome. Before the advent of molecular genetics, linkage was often studied with regard to proteins, enzymes, or cellular characteristics. An early study demonstrated linkage between the Duffy blood group and a form of autosomal dominant congenital cataract (both are now known to reside at 1q21.1). Phenotypes may also be linked in this manner (ie, families manifesting two distinct Mendelian disorders). During the recombination phase of meiosis, genetic material is exchanged (equally) between two homologous chromosomes. Genes/ DNA sequences that are located physically close to each other are unlikely to be separated during recombination. Sequences that lie far apart on the same chromosome are more likely to be separated. For sequences that reside on different chromosomes, segregation will always be random, so that there will be a 50% chance of two markers being coinherited.

Linkage analysis

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An algorithm designed to map (ie, physically locate) an unknown gene (associated with the phenotype of interest) to a chromosomal region. Linkage analysis has been the mainstay of disease-associated gene identification for some years. The general availability of large numbers of DNA markers that are variable in the population (polymorphisms), and which therefore permit allele discrimination, has made linkage analysis a relatively rapid and dependable approach (see Figure 11). However, the method relies on the ascertainment of large families manifesting Mendelian disorders. Relatively little phenotypic Genetics for Pediatricians

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36.3 36.2 36.1 35 34.3 34.2 34.1 33 32.3 32.2 32.1

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Figure 10. Schematic of a normal human (male) karyotype. (ISCN 550 ideogram produced by the MRC Human Genetics Unit, Edinburgh, reproduced with permission.)

heterogeneity is tolerated, as a single misassigned individual (believed to be unaffected despite being a gene carrier) in a pedigree may completely invalidate the results. Genetic heterogeneity is another problem, not within families (usually) but between families. Thus, conditions that result in identical phenotypes despite being associated with mutations within different genes (eg, tuberous sclerosis) are often hard to study. Linkage analysis typically follows a standard algorithm: 1. Large families with a given disorder are ascertained. Detailed clinical evaluation results in assignment of affected vs. unaffected individuals. 2. Large numbers of polymorphic DNA markers that span the genome are analyzed in all individuals (affected and unaffected). 3. The results are analyzed statistically, in the hope that one of the markers used will have demonstrably been coinherited with the phenotype in question more often than would be predicted by chance.

Glossary

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5kb 2kb

2kb

5kb 2kb

5kb 2kb

5kb 2kb

2kb

5kb 2kb

2kb

2kb

2kb

In the example above, note that the (affected) mother has a 5-kb band in addition to a 2-kb band. All the unaffected individuals have the small band only, all those who are affected have the large band. The unaffected individuals must have the mother’s 2-kb fragment rather than her 5-kb fragment, and the affected individuals must have inherited the 5-kb band from the mother (as the father does not have one) – note that those individuals who only show the 2-kb band still have two alleles (one from each parent), they are just the same size and so cannot be differentiated. Thus, it appears that the 5-kb band is segregating with the disorder. The results in a family such as this are suggestive but further similar results in other families would be required for a sufficiently high LOD score.

X

2kb

X

3kb

X

Probe

The probe recognizes a DNA sequence adjacent to a restriction site (see arrow) that is polymorphic (present on some chromosomes but not others). When such a site is present, the DNA is cleaved at that point and the probe detects a 2-kb fragment. When absent, the DNA is not cleaved and the probe detects a fragment of size (2 + 3) kb = 5 kb. X refers to the points at which the restriction enzyme will cleave the DNA. The recognition sequence for most restriction enzymes is very stringent – change in just one nucleotide will result in failure of cleavage. Most RFLPs result from the presence of a single nucleotide polymorphism that has altered the restriction site. Figure 11. Schematic demonstrating the use of restriction fragment length polymorphisms (RFLPs) in linkage analysis.

The LOD score (logarithm of the odds) gives an indication of the likelihood of the result being significant (and not having occurred simply as a result of chance coinheritance of the given marker with the condition). Linkage disequilibrium

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Association of particular DNA sequences with each other, more often than is likely by chance alone (see Figure 12). Of particular relevance to inbred populations (eg, Finland), where specific disease mutations are found to reside in close proximity to specific variants of DNA markers, as a result of the founder effect. Genetics for Pediatricians

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Marker A

Marker B

–

+

–

–

+

+

+

–

Mutant allele

Many generations

+

–

–

–

Mutant allele

Mutant allele

Figure 12. Schematic demonstrating the concept of linkage disequilibrium. A gene is physically very close to marker B and further from marker A. Markers A and B, both on the same chromosome, can exist in one of two forms : +/–. Thus there are four possible haplotypes, as shown. If the founder mutation in the gene occurred as shown, then it is likely that even after many generations the mutant allele will segregate with the – form of marker B, as recombination is unlikely to have occurred between the two. However, since marker A is further away, the gene will now often segregate with the – form of marker A, which was not present on the original chromosome. The likelihood of recombination between the gene and marker A will depend on the physical distance between them, and on rates of recombination. It is possible that the gene would show a lesser but still significant degree of linkage disequilibrium with marker A.

Linkage map

A map of genetic markers as determined by genetic analysis (ie, recombination analysis). May differ markedly from a map determined by actual physical relationships of genetic markers, because of the variability of recombination.

Locus

The position of a gene/DNA sequence on the genetic map. Allelic genes/sequences are situated at identical loci in homologous chromosomes.

Locus heterogeneity Mutations at different loci cause similar phenotypes.

Glossary

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LOD (Logarithm of the Odds) score

A statistical test of linkage. Used to determine whether a result is likely to have occurred by chance or to truly reflect linkage. The LOD score is the logarithm (base 10) of the likelihood that the linkage is meaningful. A LOD score of 3 implies that there is only a 1:1,000 chance that the results have occurred by chance (ie, the result would be likely to occur once by chance in 1,000 simultaneous studies addressing the same question). This is taken as proof of linkage (see Figure 11).

Lyonization

The inactivation of n–1 X chromosomes on a random basis in an individual with n X chromosomes. Named after Mary Lyon, this mechanism ensures dosage compensation of genes encoded by the X chromosome. X chromosome inactivation does not occur in normal males who possess only one X chromosome, but does occur in one of the two X chromosomes of normal females. In males who possess more than one X chromosome (ie, XXY, XXXY, etc.), the rule is the same and only one X chromosome remains active. X-inactivation occurs in early embryonic development and is random in each cell. The inactivation pattern in each cell is faithfully maintained in all daughter cells. Therefore, females are genetic mosaics, in that they possess two populations of cells with respect to the X chromosome: one population has one X active, while in the other population the other X is active. This is relevant to the expression of X-linked disease in females.

M Meiosis

The process of cell division by which male and female gametes (germ cells) are produced. Meiosis has two main roles. The first is recombination (during meiosis I). The second is reduction division. Human beings have 46 chromosomes, and each is conceived as a result of the union of two germ cells; therefore, it is reasonable to suppose that each germ cell will contain only 23 chromosomes (ie, the haploid number). If not, then the first generation would have 92 chromosomes, the second 184, etc. Thus, at meiosis I, the number of chromosomes is reduced from 46 to 23.

Mendelian inheritance

Refers to a particular pattern of inheritance, obeying simple rules: each somatic cell contains two genes for every characteristic and each pair of genes divides independently of all other pairs at meiosis.

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A catalogue of human Mendelian disorders, initiated in book form by Dr Victor McKusick of Johns Hopkins Hospital in Baltimore, USA. The original catalogue (produced in the mid-1960s) listed approximately 1500 conditions. By December 1998, this number had risen to 10,000 and by November 2003 the figure had reached 14,897. With the advent of the Internet, MIM is now available as an online resource, free of charge (OMIM – Online Mendelian Inheritance in Man). The URL for this site is: http://www.ncbi.nlm.nih.gov/omim/. The online version is updated frequently, far faster than is possible for the print version; therefore, new gene discoveries are quickly assimilated into the database. OMIM lists disorders according to their mode of inheritance: 1 - - - - (100000– ) Autosomal dominant (entries created before May 15, 1994) 2 - - - - (200000– ) Autosomal recessive (entries created before May 15, 1994) 3 - - - - (300000– ) X-linked loci or phenotypes 4 - - - - (400000– ) Y-linked loci or phenotypes 5 - - - - (500000– ) Mitochondrial loci or phenotypes 6 - - - - (600000– ) Autosomal loci/phenotypes (entries created after May 15, 1994). Full explanations of the best way to search the catalogue are available at the home page for OMIM.

Messenger RNA (mRNA)

The template for protein synthesis, carries genetic information from the nucleus to the ribosomes where the code is translated into protein. Genetic information flows: DNA → RNA → protein.

Methylation

See DNA methylation.

Microdeletion

Structural chromosome abnormality involving the loss of a segment that is not detectable using conventional (even high resolution) cytogenetic analysis. Microdeletions usually involve 1–3 Mb of sequence (the resolution of cytogenetic analysis rarely is better than 10 Mb). Most microdeletions are heterozygous, although some individuals/families have been described with homozygous microdeletions. See also contiguous gene syndrome.

Glossary

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Microduplication

Structural chromosome abnormality involving the gain of a segment that may involve long sequences (commonly 1–3 Mb), which are, nevertheless, undetectable using conventional cytogenetic analysis. Patients with microduplications have three copies of all sequences within the duplicated segment, as compared to two copies in normal individuals. See also contiguous gene syndrome.

Microsatellites

DNA sequences composed of short tandem repeats (STRs), such as di- and trinucleotide repeats, distributed widely throughout the genome with varying numbers of copies of the repeating units. Microsatellites are very valuable as genetic markers for mapping human genes.

Missense mutation

Single base substitution resulting in a codon that specifies a different amino acid than the wild-type.

Mitochondrial disease/disorder

Ambiguous term referring to disorders resulting from abnormalities of mitochondrial function. Two separate possibilities should be considered. 1. Mutations in the mitochondrial genome (see Figure 13). Such disorders will manifest an inheritance pattern that mirrors the manner in which mitochondria are inherited. Therefore, a mother will transmit a mitochondrial mutation to all her offspring (all of whom will be affected, albeit to a variable degree). A father will not transmit the disorder to any of his offspring. 2. Mutations in nuclear encoded genes that adversely affect mitochondrial function. The mitochondrial genome does not code for all the genes required for its maintenance; many are encoded in the nuclear genome. However, the inheritance patterns will differ markedly from the category described in the first option, and will be indistinguishable from standard Mendelian disorders. Each mitochondrion possesses between 2–10 copies of its genome, and there are approximately 100 mitochondria in each cell. Therefore, each cell possesses 200–1,000 copies of the mitochondrial genome. Heteroplasmy refers to the variability in sequence of this large number of genomes – even individuals with mitochondrial genome mutations are likely to have wild-type alleles. Variability in the proportion of molecules that are wild-type may have some bearing on the clinical variability often seen in such disorders.

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Figure 13. Mitochondrial inheritance. This pedigree relates to mutations in the mitochondrial genome.

Mitochondrial DNA

The DNA in the circular chromosome of mitochondria. Mitochondrial DNA is present in multiple copies per cell and mutates more rapidly than genomic (nuclear) DNA.

Mitosis

Cell division occurring in somatic cells, resulting in two daughter cells that are genetically identical to the parent cell.

Monogenic trait

Causally associated with a single gene.

Monosomy

Absence of one of a pair of chromosomes.

Monozygotic

Arising from a single zygote or fertilized egg. Monozygotic twins are genetically identical.

Mosaicism or mosaic Refers to the presence of two or more distinct cell lines, all derived from the same zygote. Such cell lines differ from each other as a result of DNA content/sequence. Mosaicism arises when the genetic alteration occurs postfertilization (postzygotic). The important features that need to be considered in mosaicism are: The proportion of cells that are “abnormal”. In general, the greater the proportion of cells that are abnormal, the greater the severity of the associated phenotype. The specific tissues that contain high levels of the abnormal cell line(s). This variable will clearly also be relevant to the manifestation of any phenotype. An individual may have a mutation bearing cell line in a tissue where the mutation is largely irrelevant to the normal functioning of that tissue, with a concomitant reduction in phenotypic sequelae. Mosaicism may be functional, as in normal females who are mosaic for activity of the two X chromosomes (see Lyonization).

Glossary

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Mosaicism may occasionally be observed directly. X-linked skin disorders, such as incontinentia pigmenti, often manifest mosaic changes in the skin of a female, such that abnormal skin is observed alternately with normal skin, often in streaks (Blaschko’s lines), which delineate developmental histories of cells. Multifactorial inheritance

A type of hereditary pattern resulting from a complex interplay of genetic and environmental factors.

Mutation

Any heritable change in DNA sequence.

N Nondisjunction

Failure of two homologous chromosomes to pull apart during meiosis I, or two chromatids of a chromosome to separate in meiosis II or mitosis. The result is that both are transmitted to one daughter cell, while the other daughter cell receives neither.

Nondynamic (stable) mutations

Stably inherited mutations, in contradistinction to dynamic mutations, which display variability from generation to generation. Includes all types of stable mutation (single base substitution, small deletions/ insertions, microduplications, and microdeletions).

Nonpenetrance

Failure of expression of a phenotype in the presence of the relevant genotype.

Nonsense mutation

A single base substitution resulting in the creation of a stop codon (see Figure 14).

Northern blot

Hybridization of a radiolabeled RNA/DNA probe to an immobilized RNA sequence. So called in order to differentiate it from Southern blotting, which was described first. Neither has any relationship to points on the compass. Southern blotting was named after its inventor Ed Southern

Nucleotide

A basic unit of DNA or RNA consisting of a nitrogenous base – adenine, guanine, thymine, or cytosine in DNA, and adenine, guanine, uracil, or cytosine in RNA. A nucleotide is composed of a phosphate molecule and a sugar molecule – deoxyribose in DNA and ribose in RNA. Many thousands or millions of nucleotides link to form a DNA or RNA molecule.

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A C T

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G T C

C T C

T G A

G

Collagen IIα1 sequence

Mutant (protein)

ACT Thr

GTC Val

CTC Leu

TGA STOP

Normal (protein)

ACT Thr

GTC Val

CTC Leu

TGC Cys

Figure 14. Nonsense mutation. This example shows a sequence graph of collagen II (α1) in a patient with Stickler syndrome, an autosomal dominant condition. The sequence is of genomic DNA and shows both normal and abnormal sequences (the patient is heterozygous for the mutation). The base marked with an arrow has been changed from C to A. When translated the codon is changed from TGC (cysteine) to TGA (stop). The premature stop codon in the collagen gene results in Stickler syndrome.

O Obligate carrier

See obligate heterozygote.

Obligate heterozygote (obligate carrier)

An individual who, on the basis of pedigree analysis, must carry the mutant allele.

Oncogene

A gene that, when over expressed, causes neoplasia. This contrasts with tumor suppressor genes, which result in tumorigenesis when their activity is reduced.

P p

Glossary

Short arm of a chromosome (from the French petit) (see Figure 4).

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Palindromic sequence

A DNA sequence that contains the same 5´ to 3´ sequence on both strands. Most restriction enzymes recognize palindromic sequences. An example is 5´–AGATCT–3´, which would read 3´–TCTAGA–5´ on the complementary strand. This is the recognition site of BglII.

Pedigree

A schematic for a family indicating relationships to the proband and how a particular disease or trait has been inherited (see Figure 15).

Penetrance

An all-or-none phenomenon related to the proportion of individuals with the relevant genotype for a disease who actually manifest the phenotype. Note the difference between penetrance and variable expressivity.

Phenotype

Observed disease/abnormality/trait. An all-embracing term that does not necessarily imply pathology. A particular phenotype may be the result of genotype, the environment or both.

Physical map

A map of the locations of identifiable landmarks on DNA, such as specific DNA sequences or genes, where distance is measured in base pairs. For any genome, the highest resolution map is the complete nucleotide sequence of the chromosomes. A physical map should be distinguished from a genetic map, which depends on recombination frequencies.

Plasmid

Found largely in bacterial and protozoan cells, plasmids are autonomously replicating, extrachromosomal, circular DNA molecules that are distinct from the normal bacterial genome and are often used as vectors in recombinant DNA technologies. They are not essential for cell survival under nonselective conditions, but can be incorporated into the genome and are transferred between cells if they encode a protein that would enhance survival under selective conditions (eg, an enzyme that breaks down a specific antibiotic).

Pleiotropy

Diverse effects of a single gene on many organ systems (eg, the mutation in Marfan’s syndrome results in lens dislocation, aortic root dilatation, and other pathologies).

Ploidy

The number of sets of chromosomes in a cell. Human cells may be haploid (23 chromosomes, as in mature sperm or ova), diploid (46 chromosomes, seen in normal somatic cells), or triploid (69 chromosomes, seen in abnormal somatic cells, which results in severe congenital abnormalities).

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Male, female - unaffected

Abortion/stillbirth

Sex not known

Twins

Male, female – affected

Monozygotic twins

4 unaffected females

Heterozygote (AR)

Deceased, affected female

Heterozygote (X-linked)

Consanguineous marriage

Propositus/proband

Figure 15. Symbols commonly used in pedigree drawing.

Point mutation

Single base substitution.

Polygenic disease

Disease (or trait) that results from the simultaneous interaction of multiple gene mutations, each of which contributes to the eventual phenotype. Generally, each mutation in isolation is likely to have a relatively minor effect on the phenotype. Such disorders are not inherited in a Mendelian fashion. Examples include hypertension, obesity, and diabetes.

Polymerase chain reaction (PCR)

A molecular technique for amplifying DNA sequences in vitro (see Figure 16). The DNA to be copied is denatured to its single strand form and two synthetic oligonucleotide primers are annealed to complementary regions of the target DNA in the presence of excess deoxynucleotides and a heat-stable DNA polymerase. The power of PCR lies in the exponential nature of amplification, which results from repeated cycling of the “copying” process. Thus, a single molecule will be copied in the first cycle, resulting in two molecules. In the second cycle, each of these will also be copied, resulting in four copies. In theory, after n cycles, there will be 2n molecules for each starting molecule. In practice, this theoretical limit is rarely reached, mainly for technical reasons. PCR has become a standard technique in molecular biology research as well as routine diagnostics.

Glossary

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Polymorphism

May be applied to phenotype or genotype. The presence in a population of two or more distinct variants, such that the frequency of the rarest is at least 1% (more than can be explained by recurrent mutation alone). A genetic locus is polymorphic if its sequence exists in at least two forms in the population.

Premutation

Any DNA mutation that has little, if any, phenotypic consequence but predisposes future generations to the development of full mutations with phenotypic sequelae. Particularly relevant in the analysis of diseases associated with dynamic mutations.

Proband (propositus) The first individual to present with a disorder through which a pedigree – index case can be ascertained. Probe

General term for a molecule used to make a measurement. In molecular genetics, a probe is a piece of DNA or RNA that is labeled and used to detect its complementary sequence (eg, Southern blotting).

Promoter region

The noncoding sequence upstream (5´) of a gene where RNA polymerase binds. Gene expression is controlled by the promoter region both in terms of level and tissue specificity.

Protease

An enzyme that digests other proteins by cleaving them into small fragments. Proteases may have broad specificity or only cleave a particular site on a protein or set of proteins.

Protease inhibitor

A chemical that can inhibit the activity of a protease. Most proteases have a corresponding specific protease inhibitor.

Proto-oncogene

A misleading term that refers to genes that are usually involved in signaling and cell development, and are often expressed in actively dividing cells. Certain mutations in such genes may result in malignant transformation, with the mutated genes being described as oncogenes. The term proto-oncogene is misleading because it implies that such genes were selected for by evolution in order that, upon mutation, cancers would result because of oncogenic activation. A similar problem arises with the term tumor suppressor gene.

Pseudogene

Near copies of true genes. Pseudogenes share sequence homology with true genes, but are inactive as a result of multiple mutations over a long period of time.

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3'

5'

5'

3' 95°C

DENATURATION

3'

5' P1

P2

1st Cycle

5'

3'

3'

5'

5'

3'

3'

5'

5'

3'

2nd Cycle

Genomic doublestranded DNA

P2

P1

Temperature is lowered to ~50°C to permit annealing of primers to their complementary DNA sequence Temperature is elevated to the optimal heat (~72°C) for the thermophilic polymerase, resulting in primer extension

Denaturation and annealing of primers

3'

Figure 16. Schematic illustrating the technique of polymerase chain reaction (PCR).

Purine

A nitrogen-containing, double-ring, basic compound occurring in nucleic acids. The purines in DNA and RNA are adenine and guanine.

Pyrimidine

A nitrogen-containing, single-ring, basic compound that occurs in nucleic acids. The pyrimidines in DNA are cytosine and thymine, and cytosine and uracil in RNA.

Q q

Long arm of a chromosome (see Figure 4).

R Re-annealing

See hybridization

Recessive (traits, diseases)

Manifest only in homozygotes. For the X chromosome, recessivity applies to males who carry only one (mutant) allele. Females who carry X-linked mutations are generally heterozygotes and, barring unfortunate X-inactivation, do not manifest X-linked recessive phenotypes.

Glossary

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Reciprocal translocation

The exchange of material between two non-homologous chromosomes.

Recombination

The creation of new combinations of linked genes as a result of crossing over at meiosis (see Figure 6).

Recurrence risk

The chance that a genetic disease, already present in a member of a family, will recur in that family and affect another individual.

Restriction enzyme

Endonuclease that cleaves double-stranded (ds)DNA at specific sequences. For example, the enzyme BglII recognizes the sequence AGATCT, and cleaves after the first A on both strands. Most restriction endonucleases recognize sequences that are palindromic – the complementary sequence to AGATCT, read in the same orientation, is also AGATCT. The term “restriction” refers to the function of these enzymes in nature. The organism that synthesizes a given restriction enzyme (eg, BglII) does so in order to “kill” foreign DNA – ”restricting” the potential of foreign DNA that has become integrated to adversely affect the cell. The organism protects its own DNA from the restriction enzyme by simultaneously synthesizing a specific methylase that recognizes the same sequence and modifies one of the bases, such that the restriction enzyme is no longer able to cleave. Thus, for every restriction enzyme, it is likely that a corresponding methylase exists, although in practice only a relatively small number of these have been isolated.

Restriction fragment A restriction fragment is the length of DNA generated when DNA is length polymorphism cleaved by a restriction enzyme. Restriction fragment length varies (RFLP) when a mutation occurs within a restriction enzyme sequence. Most commonly the polymorphism is a single base substitution, but it may also be a variation in length of a DNA sequence due to variable number tandem repeats (VNTRs). The analysis of the fragment lengths after DNA is cut by restriction enzymes is a valuable tool for establishing familial relationships and is often used in forensic analysis of blood, hair, or semen (see Figure 11). Restriction map

A DNA sequence map, indicating the position of restriction sites.

Reverse genetics

Identification of the causative gene for a disorder, based purely on molecular genetic techniques, when no knowledge of the function of the gene exists (the case for most genetic disorders).

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Reverse transcriptase Catalyses the synthesis of DNA from a single-stranded RNA template. Contradicted the central dogma of genetics (DNA → RNA → protein) and earned its discoverers the Nobel Prize in 1975. RNA (ribonucleic acid)

RNA molecules differ from DNA molecules in that they contain a ribose sugar instead of deoxyribose. There are a variety of types of RNA (including messenger RNA, transfer RNA, and ribosomal RNA) and they work together to transfer information from DNA to the protein-forming units of the cell.

Robertsonian translocation

A translocation between two acrocentric chromosomes, resulting from centric fusion. The short arms and satellites (chromosome segments separated from the main body of the chromosome by a constriction and containing highly repetitive DNA) are lost.

S Second hit hypothesis See tumor suppressor gene Segmental aneusomy A general term designed to encompass microdeletion/microduplication syndrome (SAS) syndrome, contiguous gene syndrome, and any situation that results in loss of function of a group of genes at a particular chromosome location, irrespective of genomic copy number (ie, loss of function may be related to mutations in master control regions, which affect the expression of many genes). See also contiguous gene syndrome. Sex chromosomes

Refers to the X and Y chromosomes. All normal individuals possess 46 chromosomes, of which 44 are autosomes and two are sex chromosomes. An individual’s sex is determined by his/her complement of sex chromosomes. Essentially, the presence of a Y chromosome results in the male phenotype. Males have an X and a Y chromosome, while females possess two X chromosomes. The Y chromosome is small and contains relatively few genes, concerned almost exclusively with sex determination and/or sperm formation. By contrast, the X chromosome is a large chromosome that possesses many hundreds of genes.

Sex-limited trait

A trait/disorder that is almost exclusively limited to one sex and often results from mutations in autosomal genes. A good example of a sex-limited trait is breast cancer. While males are affected by breast cancer, it is much less common (~1%) than in women. Females

Glossary

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are more prone to breast cancer than males, not only because they possess significantly more breast tissue, but also because their hormonal milieu is significantly different. In many cases, early onset bilateral breast cancer is associated with mutations either in BRCA1 or BRCA2, both autosomal genes. An example of a sex-limited trait in males is male pattern baldness, which is extremely rare in premenopausal women. The inheritance of male pattern baldness is consistent with autosomal dominant, not sex-linked dominant, inheritance. Sex-linked dominant See X-linked dominant Sex-linked recessive See X-linked recessive Sibship

The relationship between the siblings in a family.

Silent mutation

One that has no (apparent) phenotypic effect.

Single gene disorder A disorder resulting from a mutation on one gene. Somatic cell

Any cell of a multicellular organism not involved in the production of gametes.

Southern blot

Hybridization with a radiolabeled RNA/DNA probe to an immobilized DNA sequence (see Figure 17). Named after Ed Southern (currently Professor of Biochemistry at Oxford University, UK), the technique has spawned the nomenclature for other types of blot (Northern blots for RNA and Western blots for proteins).

Splicing

Removal of introns from precursor RNA to produce messenger RNA (mRNA). The process involves recognition of intron–exon junctions and specific removal of intronic sequences, coupled with reconnection of the two strands of DNA that formerly flanked the intron.

Start codon

The AUG codon of messenger RNA recognized by the ribosome to begin protein production.

Stop codon

The codons UAA, UGA, or UAG on messenger RNA (mRNA) (see Table 2). Since no transfer RNA (tRNA) molecules exist that possess anticodons to these sequences, they cannot be translated. When they occur in frame on an mRNA molecule, protein synthesis stops and the ribosome releases the mRNA and the protein.

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A

B

Figure 17. Southern blotting.

Synergistic heterozygosity

This refers to the phenomenon whereby the manifestation of a phenotype normally associated with complete loss of function of a single gene (ie, that gene has two mutations) may be associated with heterozygous mutations in two distinct genes that inhabit the same or related pathways.

T Telomere

End of a chromosome. The telomere is a specialized structure involved in replicating and stabilizing linear DNA molecules.

Teratogen

Any external agent/factor that increases the probability of congenital malformations. A teratogen may be a drug, whether prescribed or illicit, or an environmental effect, such as high temperature. The classical example is thalidomide, a drug originally prescribed for morning sickness, which resulted in very high rates of congenital malformation in exposed fetuses (especially limb defects).

Termination codon

See stop codon.

Glossary

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RNA polymerase

CTC

Sense strand

DNA 3' CUC GAG

Antisense strand

5' RNA

Figure 18. Schematic demonstrating the process of transcription. The sense strand has the sequence CTC (coding for leucine). RNA is generated by pairing with the antisense strand, which has the sequence GAG (the complement of CTC). The RNA produced is the complement of GAG, CUC (essentially the same as CTC, uracil replaces thymine in RNA).

Thymine (T)

One of the bases making up DNA and RNA (pairs with adenine).

Transcription

Synthesis of single-stranded RNA from a double-stranded DNA template (see Figure 18).

Transfer RNA (tRNA)

An RNA molecule that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which that codon specifies. When the ribosome “reads” the mRNA codon, the tRNA with the corresponding anticodon and amino acid is recruited for protein synthesis. The tRNA “gives up” its amino acid to the production of the protein.

Translation

Protein synthesis directed by a specific messenger RNA (mRNA), (see Figure 19). The information in mature mRNA is converted at the ribosome into the linear arrangement of amino acids that constitutes a protein. The mRNA consists of a series of trinucleotide sequences, known as codons. The start codon is AUG, which specifies that methionine should be inserted. For each codon, except for the stop codons that specify the end of translation, a transfer RNA (tRNA) molecule exists that possesses an anticodon sequence (complementary to the codon in mRNA) and the amino acid which that codon specifies. The process of translation results in the sequential addition of amino acids to the growing polypeptide chain. When translation is complete, the protein is released from the ribosome/mRNA complex and may

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LEU tRNA with anticodon GAG, charged with Leucine

Amino (NH2) terminus of protein

GAG CUCGUC 5'

3' mRNA

Ribosome

Ribosome moves to next codon

Figure 19. Schematic of the process of translation. Messenger RNA (mRNA) is translated at the ribosome into a growing polypeptide chain. For each codon, there is a transfer RNA (tRNA) molecule with the anticodon and the appropriate amino acid. Here, the amino acid leucine is shown being added to the polypeptide. The next codon is GUC, specifying valine. Translation happens in a 5´ to 3´ direction along the mRNA molecule. When the stop codon is reached, the polypeptide chain is released from the ribosome.

then undergo posttranslational modification, in addition to folding into its final, active, conformational shape. Translocation

Glossary

Exchange of chromosomal material between two or more nonhomologous chromosomes. Translocations may be balanced or unbalanced. Unbalanced translocations are those that are observed in association with either a loss of genetic material, a gain, or both. As with other causes of genomic imbalance, there are usually phenotypic consequences, in particular mental retardation. Balanced translocations are usually associated with a normal phenotype, but increase the risk of genomic imbalance in offspring, with expected consequences (either severe phenotypes or lethality). Translocations are described by incorporating information about the chromosomes involved (usually but not always two) and the positions on the chromosomes at which the breaks have occurred. Thus t(11;X)(p13;q27.3) refers to an apparently balanced translocation involving chromosome 11 and X, in which the break on 11 is at 11p13 and the break on the X is at Xq27.3

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Triallelic inheritance The association of a phenotype with three mutations. The classical example is Bardet–Biedl syndrome, in which some individuals only manifest the phenotype when three independent mutations are present (two on one gene and another on one of several genes implicated in this disorder). Triallelic inheritance has been trumpeted as providing an insight into the no-man’s land that lies between Mendelian and polygenic disorders. Triplet repeats

Tandem repeats in DNA that comprise many copies of a basic trinucleotide sequence. Of particular relevance to disorders associated with dynamic mutations, such as Huntington’s chorea (HC). HC is associated with a pathological expansion of a CAG repeat within the coding region of the huntingtin gene. This repeat codes for a tract of polyglutamines in the resultant protein, and it is believed that the increase in length of the polyglutamine tract in affected individuals is toxic to cells, resulting in specific neuronal damage.

Trisomy

Possessing three copies of a particular chromosome instead of two.

Tumor suppressor genes

Genes that act to inhibit/control unrestrained growth as part of normal development. The terminology is misleading, implying that these genes function to inhibit tumor formation. The classical tumor suppressor gene is the Rb gene, which is inactivated in retinoblastoma. Unlike oncogenes, where a mutation at one allele is sufficient for malignant transformation in a cell (since mutations in oncogenes result in increased activity, which is unmitigated by the normal allele), both copies of a tumor suppressor gene must be inactivated in a cell for malignant transformation to proceed. Therefore, at the cellular level, tumor suppressor genes behave recessively. However, at the organismal level they behave as dominants, and an individual who possesses a mutation in only one Rb allele still has an extremely high probability of developing bilateral retinoblastomas. The explanation for this phenomenon was first put forward by Knudson and has come to be known as the Knudson hypothesis (also known as the second hit hypothesis). An individual who has a germ-line mutation in one Rb allele (and the same argument may be applied to any tumor suppressor gene) will have the mutation in every cell in his/her body. It is believed that the rate of spontaneous somatic mutation (defined functionally, in terms of loss of function of that gene by whatever mechanism) is of the order of one in a million per gene per cell division.

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Given that there are many more than one million retinal cells in each eye, and many cell divisions involved in retinal development, the chance that the second (wild-type) Rb allele will suffer a somatic mutation is extremely high. In a cell that has acquired a “second hit”, there will now be no functional copies of the Rb gene, as the other allele is already mutated (germ-line mutation). Such a cell will have completely lost its ability to control cell growth and will eventually manifest as a retinoblastoma. The same mechanism occurs in many other tumors, the tissue affected being related to the tissue specificity of expression of the relevant tumor suppressor gene.

U Unequal crossing over

Occurs between similar sequences on chromosomes that are not properly aligned. It is common where specific repeats are found and is the basis of many microdeletion/microduplication syndromes (see Figure 20).

Uniparental disomy (UPD)

In the vast majority of individuals, each chromosome of a pair is derived from a different parent. However, UPD occurs when an offspring receives both copies of a particular chromosome from only one of its parents. UPD of some chromosomes results in recognizable phenotypes whereas for other chromosomes there do not appear to be any phenotypic sequelae. One example of UPD is Prader–Willi syndrome (PWS), which can occur if an individual inherits both copies of chromosome 15 from their mother.

Uniparental heterodisomy

Uniparental disomy in which the two homologues inherited from the same parent are not identical. If the parent has chromosomes A,B the child will also have A,B.

Uniparental isodisomy

Uniparental disomy in which the two homologues inherited from the same parent are identical (ie, duplicates). So, if the parent has chromosomes A,B then the child will have either A,A or B,B.

Uracil (U)

A nitrogenous base found in RNA but not in DNA, uracil is capable of forming a base pair with adenine.

Glossary

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B1

A2

B2

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C1

Repeats 1 and 2 represent identical repeated sequences in different positions on the chromosome. These are likely to have no function.

C2 Equal (normal) recombination at meiosis

B1

A1 A2

A1 A2

B1

B2

C2

Product 1 Duplication of region B and all genes within it A2

C2

B2 C1 Meiotic exchange (crossing over)

C1 Unequal (abnormal) recombination at meiosis B2

B1

C1

Product 2 Deletion of region B and all genes within it A1

C2

Figure 20. Schematic demonstrating (i) normal homologous recombination and (ii) homologous unequal recombination, resulting in a deletion and a duplication chromosome.

V Variable expressivity Variable expression of a phenotype: not all-or-none (as is the case with penetrance). Individuals with identical mutations may manifest variable severity of symptoms, or symptoms that appear in one organ and not in another. Variable number of tandem repeats (VNTR)

Certain DNA sequences possess tandem arrays of repeated sequences. Generally, the longer the array (ie, the greater the number of copies of a given repeat), the more unstable the sequence, with a consequent wide variability between alleles (both within an individual and between individuals). Because of their variability, VNTRs are extremely useful for genetic studies as they allow for different alleles to be distinguished.

W Western blot

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Like a Southern or Northern blot but for proteins, using a labeled antibody as a probe.

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X X-autosome translocation

Translocation between the X chromosome and an autosome.

X chromosome

See sex chromosomes.

X-chromosome inactivation

See lyonization.

X-linked

Relating to the X chromosome/associated with genes on the X chromosome.

X-linked recessive (XLR)

X-linked disorder in which the phenotype is manifest in homozygous/hemizygous individuals (see Figure 21). In practice, it is hemizygous males that are affected by X-linked recessive disorders, such as Duchenne’s muscular dystrophy (DMD). Females are rarely affected by XLR disorders, although a number of mechanisms have been described that predispose females to being affected, despite being heterozygous.

X-linked dominant

X-linked disorder that manifests in the heterozygote. XLD disorders

(XLD)

result in manifestation of the phenotype in females and males (see Figure 22). However, because males are hemizygous, they are more severely affected as a rule. In some cases, the XLD disorder results in male lethality.

Y Y chromosome

See sex chromosomes.

Z Zippering

Glossary

A process by which complementary DNA (cDNA) strands that have annealed over a short length undergo rapid full annealing along their whole length. DNA annealing is believed to occur in two main stages. A chance encounter of two strands that are complementary results in a short region of double-stranded DNA (dsDNA), which if perfectly matched, stabilizes the two single strands so that further re-annealing

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Figure 21a. X-linked recessive inheritance – A. Most X-linked disorders manifest recessively, in that heterozygous females (carriers) are unaffected and males, who are hemizygous (possess only one X chromosome) are affected. In this example, a carrier mother has transmitted the disorder to three of her sons. One of her daughters is also a carrier. On average, 50% of the male offspring of a carrier mother will be affected (having inherited the mutated X chromosome), and 50% will be unaffected. Similarly, 50% of daughters will be carriers and 50% will not be carriers. None of the female offspring will be affected but the carriers will carry the same risks to their offspring as their mother. The classical example of this type of inheritance is Duchenne muscular dystrophy.

Figure 21b. X-linked recessive inheritance – B. In this example the father is affected. Because all his sons must have inherited their Y chromosome from him and their X chromosome from their normal mother, none will be affected. Since all his daughters must have inherited his X chromosome, all will be carriers but none affected. For this type of inheritance, it is clearly necessary that males reach reproductive age and are fertile – this is not the case with Duchenne’s muscular dystrophy, which is usually fatal by the teenage years in boys. Emery-Dreifuss muscular dystrophy is a good example of this form of inheritance, as males are likely to live long enough to reproduce.

Figure 22. X-linked dominant inheritance. In X-linked dominant inheritance, the heterozygous female and hemizygous male are affected, however, the males are usually more severely affected than the females. In many cases, X-linked dominant disorders are lethal in males, resulting either in miscarriage or neonatal/infantile death. On average, 50% of all males of an affected mother will inherit the gene and be severely affected; 50% of males will be completely normal. Fifty percent of female offspring will have the same phenotype as their affected mother and the other 50% will be normal and carry no extra risk for their offspring. An example of this type of inheritance is incontinentia pigmenti, a disorder that is almost always lethal in males (males are usually lost during pregnancy).

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of their specific sequences proceeds extremely rapidly. The initial stage is known as nucleation, while the second stage is called zippering. Zygote

Glossary

Diploid cell resulting from the union of male and female haploid gametes.

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17 Index

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Page numbers in italics indicate tables. Page numbers in bold indicate figures. vs indicates a comparison or differential diagnosis. ABCD1 63–4 ACADM 210 acetylhydrolase 1B 46–7 achondrogenesis II 122 achondroplasia 108–10 acrocephalosyndactyly type I see Apert syndrome type III see Saethre–Chotzen syndrome (SCS) type V see Pfeiffer syndrome acrocephaly 144 acylcarnitines 211 ADA 206, 206–7 ADAMTS2 112 Addison disease 62 adenosine deaminase (ADA) deficiency 205–7 adrenal carcinoma 221 adrenal steroid 21-hydroxylase 161–2 adrenoleukodystrophy, X-linked 62–4 adrenomyeloneuropathy (AMN) 62 adult nonnephropathic cystinosis 223–5 adult polycystic kidney disease type 1 (APKD1) 226–7 type 2 (APKD2) 226–8 AE1 hereditary elliptocytosis 189 hereditary renal tubular acidosis 192 hereditary spherocytosis 191 Southeast Asian ovalocytosis 192 agammaglobulinemia, X-linked see Bruton agammaglobulinemia aganglionic megacolon see Hirschsprung disease agenesis of the corpus callosum, X-linked 67 agyria spectrum see lissencephaly AIPL1 76, 77, 78 AIS (androgen insensitivity syndrome) 158–9 Alagille syndrome 174–5 Albright’s hereditary osteodystrophy (AHO) (pseudohypoparathyroidism) 169–71 aldosterone synthesis 161 congenital adrenal hyperplasia 160 aldosterone synthetase deficiency 162 α1-antitrypsin deficiency 175–7 α-fetoprotein (AFP) 2 Alport syndrome (AS) 218–20 genes 122 androgen insensitivity syndrome (AIS) 158–9 androgen receptor androgen insensitivity syndrome 158–9 Sotos syndrome 154 anemia 193 Angelman syndrome (AS) 30–3 Rett syndrome vs 31, 62 anion exchange member 1 hereditary elliptocytosis 189 hereditary spherocytosis 191 aniridia 70–2 ANK1 191 ankyrin 1 191 α1-antitrypsin deficiency 175–7 Antly–Bixler syndrome 147 Apert syndrome 144–6 fibroblast growth factor receptors 145 AQP2 163 aquaporin-2 163, 164

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aqueduct stenosis, X-linked (X-linked hydrocephalus) 66–8 AR androgen insensitivity syndrome 158–9 CAG repeat 159 areflexia 10, 11, 27 arginine vasopressin (AVP) 163, 163–4 arginine vasopressin receptor 2 163, 164 aristaless-related homeobox protein 48 artemin 95 arterio-hepatic disorder (Alagille syndrome) 174–5 arthrochalasis multiplex congenita 112 arthro-ophthalmopathy, hereditary (Stickler syndrome) 122, 125–7 ARX 47, 48, 50 AS see Alport syndrome (AS); Angelman syndrome (AS) ASM1 (H19) 221 ASM1(H19) 223 asplenia with cardiovascular anomalies (laterality defects) 137–8 ataxia–telangiectasia (AT) 2–4 ATB7B 216 ATM 2–4 ATP7A Ehlers–Danlos syndrome 112 Menkes disease 212 atrial septal defects (ASDs) Holt–Oram syndrome 136 laterality defects 137 Noonan syndrome 138 ATR-X syndrome 64–6 autosomal dominant hyperplasia 81 autosomal dominant keratitis 71 autosomal recessive polycystic kidney disease (ARKPD) 226–8 AVP 163, 163–4 AVPR2 163, 164 bacterially expressed kinase (BEK) 145, 147 Bardet–Biedl syndrome (BBS) 72–4 bare lymphocyte syndrome 206 Barth syndrome 130 Batten disease see neuronal ceroid lipofucinosis (NCL) BBS (Bardet–Biedl syndrome) 72–4 BBS1 72, 73 BBS2 72, 73 BBS4 72, 73 BBS6 73 B-cell lymphomas 2 Beals’ syndrome 119 Beare–Stevenson cutis gyrata syndrome 147 Becker muscular dystrophy 5–6 Beckwith–Wiedemann syndrome (BWS) 220–3 Bethlem myopathy 122 bilateral pseudoglioma 79 birth weights, Sotos syndrome 153 bone marrow failure, Fanconi anemia 182 Bourneville–Pringle syndrome (tuberous sclerosis) 101–3 brachycephaly Apert syndrome 144 Saethre–Chotzen syndrome 151 brain tumors, retinoblastoma 100 BRCA2 183 bronchiectasis, primary ciliary dyskinesia 139 Bruton agammaglobulinemia 202–3 associated with growth hormone deficiency 203 Bruton tyrosine kinase 202–3 BTK Bruton agammaglobulinemia 202–3 growth hormone deficiency 165

Index

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butterfly vertebrae, Alagille syndrome 174 BWS (Beckwith-Wiedemann syndrome) 220–3 cadherin 23 nonsyndromal hearing loss 84 Usher syndrome 89 café-au-lait macules 96 CAG repeat, AR 159 CAH (congenital adrenal hyperplasia) 160–2, 162 calpain 3 19, 20 cancer 93–105 CAPN3 19, 20 carcinoembryonic antigen 2 cardiomyopathy hypertrophic, Noonan syndrome 138 X-linked 6 cardio-respiratory disorders 129–42 cartilage oligomeric matrix protein 124–5 “cascade screening”, cystic fibrosis 133 cataracts, congenital 71 catecholamines 96 CAV3 19, 20 caveolin 3 19, 20 CBP/CREBBP 151 CDH23 nonsyndromal hearing loss 84 Usher syndrome 89, 89–90 CDKN1C 221, 222 cerebral gigantism (Sotos syndrome) 153–4 cerebral malformations 29–68 ceruloplasmin Menkes disease 212 Wilson disease 216 CF (cystic fibrosis) 131–3 CFTR 131–3 CGD (chronic granulomatous disease) 203–5 CGG repeats, fragile X syndrome 34–6 Charcot–Marie–Tooth disease see hereditary motor and sensory neuropathy (HMSN) chondrosarcomas, hereditary multiple exostoses 115 chorea, Huntington disease 41 Christmas disease (hemophilia B) 187–8 chromosome 1 chronic granulomatous disease 204 cobblestone lissencephaly 49 collagen gene disorders 122 congenital adrenal hyperplasia 162 congenital hypomyelinating neuropathy 15 Dejerine–Sottas syndrome 14 hereditary elliptocytosis 189 hereditary motor and sensory neuropathy 13, 14, 15 hereditary spherocytosis 191 Hirschsprung disease association 179 infantile neuronal ceroid lipofucinosis 54 Leber congenital amaurosis 76 limb-girdle muscular dystrophy 20 medium chain acyl-CoA dehydrogenase deficiency 210 nonsyndromal hearing loss 84 ocular-scoliotic Ehlers–Danlos syndrome 112 Stickler syndrome II 126 Usher syndrome 89 van der Woude syndrome 155 Waardenburg syndrome 91 chromosome 2 Alport syndrome 219 arterial/vascular Ehlers–Danlos syndrome 112 Bardet–Biedl syndrome 72

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classical Ehlers–Danlos syndrome 112 collagen gene disorders 122 familial hypermobility Ehlers–Danlos syndrome 112 Hirschsprung disease association 179 holoproscencephaly 36 limb-girdle muscular dystrophy 20 nonsyndromal hearing loss 84 Waardenburg syndrome 91 chromosome 3 Bardet–Biedl syndrome 72 collagen gene disorders 122 Fanconi anemia 183 hereditary motor and sensory neuropathy 13 Hirschsprung disease association 179 limb-girdle muscular dystrophy 20 nonsyndromal hearing loss 84 panhypopituitarism 168 proximal myotonic myopathy 25 Usher syndrome 89 von Hippel–Lindau disease 104 Waardenburg syndrome 91 chromosome 4 achondroplasia 109 adult polycystic kidney disease type 2 227 Crouzon syndrome 147 fascioscapulohumeral muscular dystrophy 7 Huntington disease 42 limb-girdle muscular dystrophy 21 nonsyndromal hearing loss 84 polycystic kidney disease 227 Rieger syndrome 80 chromosome 5 dermatosparaxis Ehlers–Danlos syndrome 112 growth hormone receptor defects 167 hereditary motor and sensory neuropathy 15 Hirschsprung disease association 179 limb-girdle muscular dystrophy 20, 21 nonsyndromal hearing loss 84 panhypopituitarism 168 primary ciliary dyskinesia 140 Sotos syndrome 153 spinal muscular atrophy 27 Treacher Collins syndrome 154 Usher syndrome 89 chromosome 6 autosomal recessive polycystic kidney disease 227 collagen gene disorders 122 congenital adrenal hyperplasia 160 Fanconi anemia 183 laterality defects 137 Leber congenital amaurosis 76 limb-girdle muscular dystrophy 20 nonsyndromal hearing loss 84 polycystic kidney disease 227 Stickler syndrome III 126 chromosome 7 arthrochalasis multiplex congenita 112 chronic granulomatous disease 204 cobblestone lissencephaly 49 collagen gene disorders 122 cystic fibrosis 131 Greig syndrome 148 hereditary motor and sensory neuropathy 13 holoproscencephaly 36 limb-girdle muscular dystrophy 20 nonsyndromal hearing loss 84

Index

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osteogenesis imperfecta 120 Pendred syndrome 87 Saethre–Chotzen syndrome 151 Williams syndrome 141 chromosome 8 congenital adrenal hyperplasia 162 hereditary motor and sensory neuropathy 13, 14, 15 hereditary multiple exostoses 116 hereditary spherocytosis 191 nonsyndromal hearing loss 84 Pfeiffer syndrome 150 Waardenburg syndrome 91 chromosome 9 classical Ehlers–Danlos syndrome 112 cobblestone lissencephaly 49 collagen gene disorders 122 Fanconi anemia 183 Friedreich Ataxia 8 Fukuyama muscular dystrophy 49 holoproscencephaly 36 limb-girdle muscular dystrophy 21 nonsyndromal hearing loss 84 panhypopituitarism 168 primary ciliary dyskinesia 140 tuberous sclerosis 102 Walker–Warburg syndrome 49 chromosome 10 Apert syndrome 144 collagen gene disorders 122 congenital adrenal hyperplasia 162 congenital hypomyelinating neuropathy 15 Crouzon syndrome 147 Dejerine–Sottas syndrome 14 hereditary motor and sensory neuropathy 13, 14, 15 Hirschsprung disease association 179 multiple endocrine neoplasia type 2 94 nonsyndromal hearing loss 84 Pfeiffer syndrome 150 Usher syndrome 89 chromosome 11 aniridia 70 ataxia–telangiectasia 2 Bardet–Biedl syndrome 72 Beckwith–Wiedemann syndrome 221, 222 Fanconi anemia 183 hereditary motor and sensory neuropathy 15 hereditary multiple exostoses 116 late infantile neuronal ceroid lipofucinosis 54 nonsyndromal hearing loss 84 sickle cell anemia 194 β-thalassemia 197 Usher syndrome 89 chromosome 12 collagen gene disorders 122 Holt–Oram syndrome 136 nephrogenic diabetes insipidus 163 Noonan syndrome 138 phenylketonuria 214 Stickler syndrome I 126 von Willebrand disease 199 chromosome 13 connexin 26 gene defect 84, 85 Fanconi anemia 183 Hirschsprung disease association 179 holoproscencephaly 36 late infantile neuronal ceroid lipofucinosis 54

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limb-girdle muscular dystrophy 20 nonsyndromal hearing loss 84 retinoblastoma 99 Rieger syndrome 80 Waardenburg syndrome 91 Wilson disease 216 chromosome 14 α1-antitrypsin deficiency 176 hereditary elliptocytosis 189 hereditary spherocytosis 191 Leber congenital amaurosis 76 nonsyndromal hearing loss 84 severe combined immunodeficiency 206 Usher syndrome 89 chromosome 15 Angelman syndrome 30, 31 Bardet–Biedl syndrome 72 limb-girdle muscular dystrophy 20 Marfan syndrome 118 nonsyndromal hearing loss 84 Prader–Willi syndrome 31, 59 chromosome 16 adult polycystic kidney disease type 1 227 Bardet–Biedl syndrome 72 chronic granulomatous disease 204 Fanconi anemia 183 hereditary motor and sensory neuropathy 13 nonsyndromal hearing loss 84 polycystic kidney disease 227 α-thalassemia 195 chromosome 17 arthrochalasis multiplex congenita 112 classical Ehlers–Danlos syndrome 112 collagen gene disorders 122 cystinosis 224 Dejerine–Sottas syndrome 14 growth hormone deficiency 165 hereditary elliptocytosis 189 hereditary motor and sensory neuropathy 13, 14, 15 hereditary neuropathy with liability to pressure palsies 15 hereditary spherocytosis 191 Leber congenital amaurosis 76 limb-girdle muscular dystrophy 20, 21 lissencephaly 48 Miller–Dieker syndrome 48 neurofibromatosis type 1 97 nonsyndromal hearing loss 84 osteogenesis imperfecta 120 Usher syndrome 89 chromosome 18, holoproscencephaly 36 chromosome 19 Dejerine–Sottas syndrome 14 hereditary motor and sensory neuropathy 14 hereditary multiple exostoses 116 Hirschsprung disease association 179 Leber congenital amaurosis 76 limb-girdle muscular dystrophy 21 myotonic dystrophy 25 pseudoachondrodysplasia 124 chromosome 20 adenosine deaminase deficiency 206 Alagille syndrome 174 Bardet–Biedl syndrome 72 collagen gene disorders 122 Hirschsprung disease association 179 neurohypophyseal diabetes insipidus 163

Index

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pseudohypoparathyroidism 171 severe combined immunodeficiency 206 Waardenburg syndrome 91 chromosome 21 collagen gene disorders 122 holoproscencephaly 36 nonsyndromal hearing loss 84 Usher syndrome 89 chromosome 22 DiGeorge/Shprintzen syndrome 134 Hirschsprung disease association 179 nonsyndromal hearing loss 84 Waardenburg syndrome 91 chromosome analysis aniridia 71 lissencephaly 51 chronic granulomatous disease (CGD) 203–5 classic hemophilia (hemophilia A) 185–7 claudin 14 84 CLDN14 84 clear cell renal cell carcinomas, von Hippel–Lindau disease 103 cleft lip/palate, van der Woude syndrome 155 clinical examination Ehlers–Danlos syndrome 114 tuberous sclerosis 103 CLN1 54, 55 CLN2 54, 56 CLN3 54, 56 CLN5 54, 56–7 Coat’s disease 79 cobblestone lissencephaly 46 COCH 84 cochlin 84 COL1A1 Ehlers–Danlos syndrome 112, 113–4, 122 osteogenesis imperfecta 120–1, 122 osteoporosis 122 COL1A2 Ehlers–Danlos syndrome 112, 113–4, 122 osteogenesis imperfecta 120–1, 122 osteoporosis 122 COL2A1 122, 126–7 Stickler syndrome I 122, 126, 126 COL3A1 112, 113, 122 COL4A3 122, 218–20, 219 COL4A4 122, 218–9, 219 COL4A5 122, 218–20, 219 COL4A6 Alport syndrome 219 leiomyomatosis 122 COL5A1 111, 112, 113–4, 122 COL5A2 111, 112, 113–4, 122 COL6A1 122 COL6A2 122 COL6A3 122 COL7A1 122 COL9A1 122 COL9A2 122 COL9A3 122 COL10A1 122 COL11A1 122, 126, 127 COL11A2 nonsyndromal hearing loss 84 Stickler syndrome III 122, 126, 127 Weissenbacher–Zweymuller syndrome 122 COL17A1 122

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COL18A1 122 collagen type IIα2 84 type IV 218–20 combined pituitary hormone deficiency (panhypopituitarism) 167–9 COMP 124–5 congenital adrenal hyperplasia (CAH) 160–2, 162 congenital cataracts 71 congenital central hyperventilation syndrome 95 congenital hypomyelinating neuropathy (CHN) 11, 15 congenital intestinal aganglionosis see Hirschsprung disease congenital lipoid adrenal hyperplasia 162 connective tissue disorders 107–27 connexin 26/30 84 26 gene defect 85–6 31 84 conotruncal anomaly facial syndrome (DiGeorge/Shprintzen syndrome) 133–5 convulsions, Angelman syndrome 30 Cooley’s anemia (β-thalassemia) 197–8 copper deficiency, Menkes disease 211 copper deposition, Wilson disease 215–6 copper-transporting ATPase Menkes disease 212 Wilson disease 216 cortisol synthesis 161 congenital adrenal hyperplasia 160 craniofacial disorders 143–56 craniofacial dysostosis see Crouzon syndrome craniosynostosis Crouzon syndrome 146 Saethre–Chotzen syndrome 151 CRB1 76, 77–8 creatine kinase (CK) 6 CREBBP/CBP 151 cross-reacting material (CRM) positive, hemophilia A 186 Crouzon syndrome 146–8 FGFR2 150 fibroblast growth factor receptors 145 Crouzon syndrome with acanthosis nigricans 147–8 fibroblast growth factor receptors 145 CRX1 76, 77, 78 CTNS 224 cutaneous neurofibromas 96 cutis laxa, Ehlers–Danlos syndrome vs 110–1 CX26/30 connexin 26 gene defect 85–6 nonsyndromal hearing loss 84 CX31 84 CX32 (GLB1) 12, 13, 16, 17 CXORF5(OFDI) 225–6 CYBA 204, 204 CYBB 204, 204–5 cyclin-dependent kinase inhibitor 1C 221 CYP11B1 162 CYP11B2 162 CYP17 162 CYP21 160–2 cystic fibrosis (CF) 131–3 cystic fibrosis transmembrane conductance regulator (CFTCR) 131–3 cystinoin 224 cystinosis 223–5 cytochrome-b α-subunit 204 β-subunit 204

Index

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DCX 47, 48 DDP 84 deafness with goiter (Pendred syndrome) 86–7 Dejerine–Sottas syndrome 10 dementia, Huntington disease 41 depigmentation, Waardenburg syndrome 90 dermatosparaxis Ehlers–Danlos syndrome 112 17, 20-desmolase deficiency 159 dexamethasone, congenital adrenal hyperplasia 162 DFNA5 84 diabetes insipidus (DI) 163–4 nephrogenic 163, 164 neurohypophyseal 163, 163–4 diaphyseal aclasis (hereditary multiple exostoses) 115–7 DiGeorge/Shprintzen syndrome 133–5 dihydropteridine reductase 215 dilated cardiomyopathy Barth syndrome 130 LMNA 19 DMD 4–6 DMD (Duchenne muscular dystrophy) 4–6 DMPK 25–6 DNAH5 140 DNAI1 140 DNA methylation, Beckwith–Wiedemann syndrome 222–3 doublecortin 46–47, 48 Down’s syndrome, Hirschsprung disease association 177 Duchenne muscular dystrophy (DMD) 4–6 Dunnigan type partial lipodystrophy 19 dynein 46–47, 140, 140–1 dysarthria, Friedreich ataxia 8 DYSF 19, 20 dysferlin 19, 20 dystonia canthorum 90 dystrophia myotonica protein kinase 25–6 dystrophin 5–6 ECE1 179 eczema phenylketonuria 214 Wiskott–Aldrich syndrome 207–8 EDN3 Hirschsprung disease association 179 Waardenburg syndrome 91, 92 EDNRB Hirschsprung disease association 179 Waardenburg syndrome 91, 92 EGR2 12, 13, 14, 15 Ehlers–Danlos syndrome 110–4 cutis laxa vs 110–1 genes/chromosomal locations 112, 122 elastin 141–2 electroencephalography (EEG) adult neuronal ceroid lipofucinosis 55 infantile neuronal ceroid lipofucinosis 54 electromyography 27 electron microscopy, Ehlers–Danlos syndrome 114 electroretinography (ERG) infantile neuronal ceroid lipofucinosis 54 juvenile retinoschisis 74 elliptocytes 189–90 elliptocytosis, hereditary 189–90 ELN 141–2 Emery–Dreifuss muscular dystrophy limb-girdle muscular dystrophy vs 22–3 LMNA 19

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endocrine disorders 157–71 endothelin 3 179 endothelin-converting enzyme-1 179 endothelin receptor, type B 179 EPB41 189 epidermolysis bullosa 122 junctional 122 Epstein syndrome, Alport syndrome overlap 220 erythrocyte cytoskeleton hereditary elliptocytosis 190 hereditary spherocytosis 191–2 exomphalos-macroglossia-gigantism (EMG) syndrome (Beckwith-Wiedemann syndrome) 220–3 EXT1 hereditary multiple exostoses 116, 116–7 Langer–Giedion syndrome 117 EXT2 116, 116–7 EXT3 116 exudative vitreoretinopathy, X-linked 79 EYA4 84 F8 186–7 F9 188 facial features achondroplasia 108 Alagille syndrome 174 DiGeorge/Shprintzen syndrome 133–4 holoproscencephaly 36 Miller–Dieker syndrome 45 pseudohypoparathyroidism 169 Rubenstein–Taybi syndrome 151 Stickler syndrome 125 Treacher Collins syndrome 154 Williams syndrome 141 X-linked α-thalassemia and mental retardation syndrome 64 facioscapulohumeral muscular dystrophy (FSHMD) 7–8 limb-girdle muscular dystrophy vs 22–3 factor VIII deficiency (hemophilia A) 185–7 factor IX deficiency (hemophilia B) 187–8 Fallot’s tetralogy, DiGeorge/Shprintzen syndrome 134 familial medullary thyroid carcinoma see multiple endocrine neoplasia type 2 (MEN2) family history, Ehlers–Danlos syndrome 114 FANCA 182, 183 FANCC 182, 183 FANCD2 183 FANCE 183 FANCF 183 FANCG 183 Fanconi anemia 182–3 Fanconi pancytopenia (Fanconi anemia) 182–3 favism (glucose-6-phosphate dehydrogenase deficiency) 183–5 FBN1 118–9 FBN2 119 FCMD cobblestone lissencephaly 49 Fukuyama muscular dystrophy 49, 50–1 Fechtner syndrome, Alport syndrome overlap 220 α-fetoprotein (AFP) 2 FGFR1 150, 150 FGFR2 Antly–Bixler syndrome 147 Apert syndrome 144–6, 145, 147 Beare–Stevenson cutis gyrata syndrome 147 Crouzon syndrome 147, 147–8, 150 Jackson–Weiss syndrome 147 Pfeiffer syndrome 147, 150, 150

Index

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FGFR3 achondroplasia 109, 109–10, 110 Crouzon syndrome 147, 147–8 hypochondroplasia 109, 110 severe achondroplasia with developmental delay and acanthosis nigricans 110 thanatophoric dysplasia 109, 110 fibrillin 1 118–9 fibroblast growth factor receptors achondroplasia 109, 109–10 Apert syndrome 145 Crouzon syndrome 145 with acanthosis nigricans 145 Muenke syndrome 145 Pfeiffer syndrome 145 fibrocystin 227, 228 FKRP 21, 22 “flip inversions”, hemophilia A 186, 186, 187 fluorescence in situ hybridization (FISH) Angelman syndrome 32, 33 aniridia 71 DiGeorge/Shprintzen syndrome 134–5, 135 lissencephaly 51 neurofibromatosis type 1 97 Prader–Willi syndrome 60 Rubenstein–Taybi syndrome overlap 151 Williams syndrome 142 FMR1 34–5 14-3-3ε 47, 48 fragile X syndrome 34–6 Franceschetti’s sign, Leber congenital amaurosis 75 frataxin 9 FRDA 9 freckling, neurofibromatosis type 1 96 Friedreich Ataxia 8–9 FSHMD see facioscapulohumeral muscular dystrophy fukutin cobblestone lissencephaly 49 Fukuyama muscular dystrophy 49, 50–1 fukutin-related protein 21, 22 Fukuyama muscular dystrophy 49 G4.5 (TAZ) 130 G6PD 184–5 gait abnormalities, X-linked adrenoleukodystrophy 62 GARS 13, 16 gastrointestinal disorders 173–9 GDAP1 14, 15, 16 GDNF 179 gel electrophoresis, α1-antitrypsin deficiency 176 GH1 165, 165–6 GHR 167 GLI3 148–9 glial cell-line derived neurotrophic factor (GDNF) 95 Hirschsprung disease association 179 glucose-6-phosphate dehydrogenase deficiency 183–5 GNAS1 170, 171 Gorlin syndrome 38 granular osmophilic deposits (GRODs) 54 Greig cephalopolysyndactyly syndrome see Greig syndrome Greig syndrome 148–9 Rubenstein–Taybi syndrome overlap 151 growth hormone deficiency 164–6 receptor defects 166–7 guanine nucleotide-binding (Gs) protein 170, 171 GUCY2d 76, 77, 78

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H19 (ASM1) 221, 223 Haddad syndrome 95 happy puppet syndrome see Angelman syndrome (AS) harmonin 88, 89 HBA 195–6 HBB sickle cell anemia 194 β-thalassemia 197–8 HbH inclusions, X-linked α-thalassemia and mental retardation syndrome 65–6 HD (Huntington disease) 41–3 HD1A8 84 hearing disorders 83–92 Alport syndrome 218 heart–hand syndrome (Holt–Oram syndrome) 135–6 Heinz bodies 185 hemangioblastomas, von Hippel–Lindau disease 103 hematologic disorders 181–99 hematuria Alport syndrome 218 polycystic kidney disease 226 hemoglobin α-globin gene 196 α-thalassemia 195–7 hemoglobin β-globin gene sickle cell anemia 194 β-thalassemia 197–8 hemoglobin H (HbH) disease 194–7 hemophilia A 185–7 hemophilia B 187–8 hepatic disorders 173–9 hepatoblastoma, Beckwith–Wiedemann syndrome 221 hepato-lenticular degeneration (Wilson disease) 215–6 HERC2 60 hereditary arthro-ophthalmopathy (Stickler syndrome) 122, 125–7 hereditary elliptocytosis 189–90 hereditary motor and sensory neuropathy (HMSN) 10–7 clinical features 9–10 molecular pathogenesis 11–2, 16–7 hereditary multiple exostoses (HME) 115–7 hereditary neuropathy with liability to pressure palsies (HNPP) 11 hereditary pyropoikilocytosis 189 hereditary renal tubular acidosis 192 hereditary spherocytosis 190–2 heterotaxy (laterality defects) 137–8 hexacosanoate 64 HGPRT deficiency (Lesch–Nyhan syndrome) 43–4 Hirschsprung disease 177–9 disease association 177 RET 95 Waardenburg syndrome 92 HMSN see hereditary motor and sensory neuropathy holoproscencephaly (HPE) 36–9 Holt–Oram syndrome (HOS) 135–6 HRPT 44 HSCR see Hirschsprung disease HSD3B2 162 Hunter syndrome (HS) 40–1 huntingtin 42 Huntington disease (HD) 41–3 Hutchinson–Gilford syndrome 19 hydrocephalus, X-linked 66–8 hydrops fetalis 195–6 11β-hydroxylase deficiency 162 17α-hydroxylase deficiency 159 congenital adrenal hyperplasia 162 21-hydroxylase deficiency (congenital adrenal hyperplasia) 160–2, 162

Index

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3β-hydroxysteroid dehydrogenase deficiency 159 congenital adrenal hyperplasia 162 17β-hydroxysteroid dehydrogenase deficiency 159 hyperammonemia, ornithine transcarbamylase deficiency 212–3 hyperphosphatemia, pseudohypoparathyroidism 169 hypertrophic cardiomyopathy, Noonan syndrome 138 hypocalcemia, pseudohypoparathyroidism 169 hypochondrogenesis 122 hypochondroplasia 109, 110 hypoglycemia, medium chain acyl-CoA dehydrogenase deficiency 210 hypopigmentation Angelman syndrome 32 phenylketonuria 214 Prader–Willi syndrome 60 hypothyroidism, pseudohypoparathyroidism 169 hypotonia Pelizaeus–Merzbacher syndrome 57 Prader–Willi syndrome 59 spinal muscular atrophy 27 hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch–Nyhan syndrome) 43–4 IDS 40–1 iduronate 2-sulfatase 40–1 IGF2 221, 223 IL2RG 206, 207 immotile cilia syndrome see primary ciliary dyskinesia immunoglobulin levels, ataxia–telangiectasia 2 immunohistochemistry Duchenne muscular dystrophy 6 limb-girdle muscular dystrophy 22 immunologic disorders 201–8 imprinting Beckwith–Wiedemann syndrome 222–3 Prader–Willi syndrome 60 pseudohypoparathyroidism 170 infantile hypercalcemia (Williams syndrome [WS]) 141–2 infantile nephropathic cystinosis 223–5 infantile Refsum disease 76 infantile spasms, X-linked 50 infections sickle cell anemia 193 Wiskott–Aldrich syndrome 207–8 insulin-like growth factor (IGF)1 166 insulin-like growth factor (IGF)2 221 interferon regulatory factor 6 155–6 interleukin-2 receptor, γ chain 206, 207 intestinal aganglionosis, congenital see Hirschsprung disease IRF6 155–6 iridogoniodysgenesis type II (Rieger syndrome) 80–1 isoelectric focusing, α1-antitrypsin deficiency 176 isolated fovea hypoplasia 71 isomerism (laterality defects) 137–8 IT15 42–3 Ivemark syndrome (laterality defects) 137–8 Jackson–Weiss syndrome 147 JAG1 174–5 jagged 1 174–5 Jansky–Bielschowski disease see neuronal ceroid lipofucinosis (NCL) jaundice Alagille syndrome 174 glucose-6-phosphate dehydrogenase deficiency 184 hereditary spherocytosis 190 Jervell syndrome 223 joint laxity, Ehlers–Danlos syndrome 110 Joubert syndrome 76

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Juberg–Marsidi syndrome 65 junctional epidermolysis bullosa 122 juvenile nephropathic cystinosis 223–5 juvenile retinoschisis 74–5 Kartagener syndrome see primary ciliary dyskinesia Kayser–Fleischer ring, Wilson disease 216 keratinocyte growth factor receptor (KGFR) Apert syndrome 145–6 Crouzon syndrome 147 KIF1B 13, 16 kinky hair disease see Menkes disease Klein–Waardenburg syndrome see Waardenburg syndrome Kneist dysplasia 122 Knobloch syndrome 122 Kufs disease see neuronal ceroid lipofucinosis (NCL) Kugelberg–Welander syndrome 27–8 KVLQT1 Beckwith–Wiedemann syndrome 221, 222–3 Jervell syndrome 223 Lange–Nielsen syndrome 223 L1CAM 67–8 L1 cell-adhesion molecule 67–8 lamin A hereditary motor and sensory neuropathy 13, 16 limb-girdle muscular dystrophy 18, 20 lamin B 16 lamin C hereditary motor and sensory neuropathy 13 limb-girdle muscular dystrophy 18 Lange–Nielsen syndrome 223 Langer–Giedion syndrome 117 Laron dwarfism (growth hormone receptor defects) 166–7 laterality defects 137–8 laughter, Angelman syndrome 30 LCA see Leber congenital amaurosis Leber congenital amaurosis (LCA) 75–9 clinical features 75–6 genes/chromosomal location 76 molecular pathogenesis 78 leiomyomatosis 122 Lesch–Nyhan syndrome 43–4 leucocoria, retinoblastoma 98 Leyden hemophilia B 188 Leydig cell hyperplasia 159 LGMD see limb-girdle muscular dystrophy LHX3 168, 168 limb-girdle muscular dystrophy (LGMD) 18–23 Emery–Dreifuss muscular dystrophy vs 22–3 fascioscapulohumeral muscular dystrophy vs 22–3 molecular pathogenesis 18–9, 22 lim homeobox 3 168 linkage analysis ataxia–telangiectasia 4 congenital adrenal hyperplasia 162 neuronal ceroid lipofucinosis 55 lipoid adrenal hyperplasia, congenital 162 lipoid congenital adrenal hyperplasia 159 lip-pit syndrome (van der Woude syndrome) 155–6 LIS1 (PAFAH1B1) lissencephaly 46–7, 48 Miller–Dieker syndrome 48 Lisch nodules, neurofibromatosis type 1 98 lissencephaly 45–51 clinical features 45–6

Index

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genes/molecular pathogenesis 46–7, 48–9, 50–1 X-linked 45 LITAF 12, 13 LMNA hereditary motor and sensory neuropathy 13, 16 limb-girdle muscular dystrophy 18–9, 20 Louis-Bar syndrome (ataxia–telangiectasia [AT]) 2–4 Lowe syndrome 52–3 17, 20-lyase deficiency 162 lysyl hydroxylase 113–4 Madelung deformity 115 magnetic resonance imaging (MRI) Pelizaeus–Merzbacher syndrome 57, 58–9 subcortical band heterotopia 45 X-linked adrenoleukodystrophy 63 X-linked hydrocephalus 66 major histocompatibility complex (MHC) deficiency 206 male pseudohermaphroditism 159 androgen insensitivity syndrome 158 malignant melanomas, retinoblastoma 100 mandibuloacral dysplasia 19 mandibulofacial dystosis (Treacher Collins syndrome) 154–5 O-mannose β-1,2-N-acetylglucosaminyltransferase-1 50 O-mannosyl transferase 1 49, 50 Marfanoid habitus, multiple endocrine neoplasia type 2 94 Marfan syndrome 117–9 Marshall syndrome 125–7 MASA syndrome 67 McCune–Albright syndrome 170 Mckusick–Kaufman syndrome 72, 73 MD (myotonic dystrophy) 23–6 MECP2 61–2 medium chain acyl-CoA dehydrogenase deficiency 210–1 melanomas, malignant, retinoblastoma 100 MEN2 see multiple endocrine neoplasia type 2 Menkes disease 211–2 Ehlers–Danlos syndrome 114 mental retardation 29–68 phenylketonuria 214 X-linked 50 metabolic disorders 209–16 metaphyseal chondrodysplasia 122 methylation analysis Angelman syndrome 32, 33 Prader–Willi syndrome 60 methyl-CpG-binding protein 2 61–2 3α-methylglutaconic aciduria II (Barth syndrome) 130 microhematuria, Alport syndrome 220 Miller–Dieker syndrome (MDS) 45, 47, 48 MITF 91, 92 MKKS 72, 73 Mowat–Wilson syndrome 179 MPZ 12, 13, 14, 15, 17 MTMR2 15, 16–7 mucopolysaccharidosis type II (MPS II) (Hunter syndrome [HS]) 40–1 mucoviscidosis (cystic fibrosis) 131–3 Muenke syndrome 150 fibroblast growth factor receptors 145 multiple cartilogenous exostoses (hereditary multiple exostoses [HME]) 115–7 multiple endocrine neoplasia type 2 (MEN2) 94–6 RET 178 multiple epiphyseal dysplasia (MED) 122, 125 multiple osteochondromatosis (hereditary multiple exostoses [HME]) 115–7 muscle weakness Duchenne muscular dystrophy 4

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myotonic dystrophy 23–4 muscular dystrophy of muscle–eye–brain disease (MEBD) 50 MYH9 84, 220 MYO3A 84 MYO6 84 MYO7A nonsyndromal hearing loss 84 Usher syndrome 88–9, 89 MYO15 84 myosin heavy chain 9 84 myosin IIIA 84 V 84 VI 84 VIIA 84, 88, 89 myotilin 18 myotonic dystrophy (MD) 23–6 myotubularin-related protein 2 16–7 NADPH oxidase 204 NCF1 204, 204 NCF2 204, 204 NCL see neuronal ceroid lipofucinosis (NCL) NDN 59–60 NDP 79–80 NDRG1 15, 17 necdin 59–60 NEFL 12, 13, 14T nephrogenic diabetes insipidus 163, 164 nephropathy and deafness see Alport syndrome (AS) nerve conduction velocities (NCVs) 10–1, 13–5 neuroblastoma, Beckwith–Wiedemann syndrome 221 neurocutaneous disorders 93–105 neurofibromatosis type 1 96–8 Noonan syndrome 139 neurofibromin 97–8 neurohypophyseal diabetes insipidus 163, 163–4 neuroimaging holoproscencephaly 39 X-linked adrenoleukodystrophy 63 neurologic disorders 1–28 neuronal ceroid lipofucinosis (NCL) 53–7 adult 54, 55 infantile 53–4, 54 juvenile 54, 54 late infantile 54, 54 neurturin 95 neutropenia, Barth syndrome 130 neutrophil cystolic factor 1 204 neutrophil cystolic factor 2 204 NF1 97–8 Nijmegen breakage syndrome 3 nonsyndromal hearing loss 84 Noonan syndrome 138–9 neurofibromatosis type 1 139 “normal transmitting males”, fragile X syndrome 35 Norrie disease 79–80 NSD1 153–4 nuclear receptor SET-domain protein I 153–4 nystagmus, Pelizaeus–Merzbacher syndrome 57 obesity, Bardet–Biedl syndrome 72 occipital horn syndrome 112 OCRL1 52–3 octocadherin 89–99 oculo-cerebro-renal syndrome (Lowe syndrome) 52–3

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oculodigital sign, Leber congenital amaurosis 75 OFD1 (orofaciodigital syndrome type I [OFD1]) 225–6 OI see osteogenesis imperfecta Ondine’s curse 95 oral-facial-digital syndrome type I (orofaciodigital syndrome type I [OFD1]) 225–6 ornithine transcarbamylase deficiency 212–4 orofaciodigital syndrome type I (OFD1) 225–6 osteoarthritis 122 osteochondrosarcomas, hereditary multiple exostoses 116–7 osteogenesis imperfecta (OI) 119–24 clinical features 120, 121 mutational mechanisms 123 radiologic features 121, 123 osteogenesis imperfecta congenita (OIC) see osteogenesis imperfecta (OI) osteogenesis imperfecta tarda (OIT) see osteogenesis imperfecta (OI) osteoporosis 122 osteosarcoma hereditary multiple exostoses 115 retinoblastoma 100 OTC 213–4 OTOA 84 otoancorin 84 OTOF 84 otoferlin 84 outwardly rectifying chloride channels 132 P1 176–7 pachygyria spectrum see lissencephaly PAFH1B1 see LIS1 (PAFAH1B1) PAH 214–5 Pallister–Hall syndrome 149 palmitoyl-protein thioesterase (PPT) 55 panhypopituitarism 167–9 Partington syndrome 50 patent ductus arteriosus, Noonan syndrome 138 paternal uniparental disomy (UPD), Beckwith–Wiedemann syndrome 221 PAX3 91, 91–2 PAX6 70–2 PCDH15 89, 90 PDS 84 PDS (Pendred syndrome) 86–7 pedigree analysis, hereditary motor and sensory neuropathy 17 Pelizaeus–Merzbacher syndrome 57–9 Pendred syndrome (PDS) 86–7 pendrin 84 periaxin 14, 16 peroneal muscular atrophy see hereditary motor and sensory neuropathy (HMSN) persephin 95 personality changes Huntington disease 41 Williams syndrome 141 Peter’s anomaly PAX6 71 PITX2 81 Pfeiffer syndrome 149–50 FGFR2 147 fibroblast growth factor receptors 145 phagocytosis, chronic granulomatous disease 203 phenylalanine decarboxylase deficiency (phenylketonuria [PKU]) 214–5 phenylketonuria (PKU) 214–5 pheochromocytomas multiple endocrine neoplasia type 2 96 von Hippel–Lindau disease 103 phosphatidylinositol-4,5-bisphosphatase 52–3 PHP (pseudohypoparathyroidism) 169–71

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Pierre Robin anomaly Stickler syndrome 125 Weissenbacher–Zweymuller syndrome 127 PIT1 168, 168 pituitary dwarfism (growth hormone deficiency) 164–6 pituitary-specific transcription factor 1 168 PITX2 80, 81 PKD1 227, 227–8 PKD2 227, 227–8 PKHD1 227, 228 PKU (phenylketonuria) 214–5 plagiocephaly, Saethre–Chotzen syndrome 151 PLOD1 112, 113 PLP1 58, 58 PMP22 11–2, 13, 14, 15, 17 PNP 206, 206–7 polycystic kidney disease (PKD) 226–8 polycystin 1 227 polycystin 2 227 polydipsia, cystinosis 224 polyhydramnios, myotonic dystrophy 24 polysplenia syndrome (laterality defects) 137–8 polyuria cystinosis 224 diabetes insipidus 163 POMGnT1 cobblestone lissencephaly 49, 50 muscular dystrophy of muscle–eye–brain disease 50 POMT1 49, 50 popliteal pterygium syndrome 156 postaxial polydactyly type A1 149 posterior embryotoxon 174 POU3F4 84 POU4F3 84 Prader–Labhardt–Willi syndrome see Prader–Willi syndrome (PWS) Prader–Willi syndrome (PWS) 30, 59–60 chromosome 15 31, 59 preaxial polydactyly type IV 149 presenile cataracts, myotonic dystrophy 23 primary ciliary dyskinesia 139–41 situs inversus 137, 140 primordial dwarfism (growth hormone deficiency) 164–6 progeria 19 progressive ataxias 1–28 PROMM (proximal myotonic myopathy) 23–6 PROP1 168, 168 prophet of POT1 168 protease inhibitor 1 176–7 protein-tyrosine phosphatase, nonreceptor-type 11 138–9 proteolipid protein 1 58 protocadherin 15 89 proximal myotonic myopathy (PROMM) 23–6 PRX 14, 16 pseudoachondrodysplasia 124–5 pseudoachondrodysplastic spondyloepiphyseal dysplasia 124–5 pseudohemophilia (von Willebrand disease) 198–9 pseudohypoparathyroidism (PHP) 169–71 pseudopseudohypoparathyroidism (PPHP) 169–71 psychomotor regression, Rett syndrome 61 PTCH Gorlin syndrome 38 holoproscencephaly 36, 38, 39 PTPN11 138–9 pulmonary stenosis Alagille syndrome 174 Noonan syndrome 138

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purine nucleoside phosphorylase (PNP) deficiency 205–7 PWS see Prader–Willi syndrome pyropoikilocytosis, hereditary 189 6-pyruvoyltetrahydropterin synthase 215 RAB7 16 radiologic examination, tuberous sclerosis 103 RAS-associated protein-7 16 RAS-MAP kinase pathway 95 RB1 99–100 receptor tyrosine kinase 179 5α-reductase deficiency 159 reelin cobblestone lissencephaly 49 lissencephaly 51 Refsum disease, infantile 76 RELN cobblestone lissencephaly 49 lissencephaly 51 renal disorders 217–26 Bardet–Biedl syndrome 72 renal Fanconi syndrome cystinosis 224 Lowe syndrome 52 renal tubular acidosis, hereditary 192 restriction fragment length polymorphism analysis (RFLP), Angelman syndrome 32 RET Haddad syndrome 95 Hirschsprung disease 95 association 178–9, 179 multiple endocrine neoplasia type 2 94–6, 178 retinal angiomas, von Hippel–Lindau disease 103 retinal dystrophy, Bardet–Biedl syndrome 72 retinal examination, juvenile neuronal ceroid lipofucinosis 54 retinitis pigmentosa Leber congenital amaurosis vs 76 Usher syndrome 87–8 retinoblastoma 98–100 retinoschisin 75 retinoschisis, X-linked (juvenile retinoschisis) 74–5 Rett syndrome 61–2 Angelman syndrome vs 31, 62 infantile neuronal ceroid lipofucinosis vs 53 rhabdomyosarcoma, Beckwith–Wiedemann syndrome 221 Rieger syndrome 80–1 RPE65 76, 77, 78 RPGRIP1 76, 77, 78 RS1 75 Rubenstein–Taybi syndrome 151 Saethre–Chotzen syndrome (SCS) 152–3 Rubenstein–Taybi syndrome overlap 151 Santavuori–Haltia–Hagberg disease see neuronal ceroid lipofucinosis (NCL) α-sarcoglycan 19, 20, 22 β-sarcoglycan 21, 22 δ-sarcoglycan 21, 22 γ-sarcoglycan 20, 22 sarcoglycanopathies 18 sarcomas, retinoblastoma 100 SBF2 15, 17 screening, von Hippel–Lindau disease 105 SCS see Saethre–Chotzen syndrome Senior–Loken syndrome 76 SET-binding factor 2 17 severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) 110 severe combined immunodeficiency (SCID) 205–7

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severe congenital neutropenia, WAS 208 sex-determining factor-related box 10 179 SGCA 19, 20 SGCB 21, 22 SGCD 21 SGCG 20 “shaker” 88 SHH 36, 37, 38 Shprintzen syndrome (DiGeorge/Shprintzen syndrome) 133–5 sickle cell anemia 193–4 sickle cell trait 193 SIP1 179 Sipple syndrome see multiple endocrine neoplasia type 2 (MEN2) situs ambiguus (laterality defects) 137–8 situs inversus Kartagener syndrome 140 primary ciliary dyskinesia 139–40 SIX3 36, 37, 38 skeletal disorders 107–27 skin hyperextensibility, Ehlers–Danlos syndrome 110 SLC26A4 87 SMA (spinal muscular atrophy) 27–8 small nucleoribonucleoprotein N 59–60 SMN1 27–8 SNRPN 59–60, 60 Sotos syndrome 153–4 Southeast Asian ovalocytosis 190, 192 SOX-10 91, 179 spastic paraparesis, X-linked 67 spastic paraplegia, X-linked 58 spectrins hereditary elliptocytosis 189 hereditary spherocytosis 191 spherocytosis, hereditary 190–2 Spielmeyer–Vogt–Sjögren disease see neuronal ceroid lipofucinosis (NCL) spinal muscular atrophy (SMA) 27–8 spondyloepimetaphyseal dysplasia (SEMD) 122 spondylopepiphyseal dysplasia congenita (SEDC) 122 SPTA1 hereditary elliptocytosis 189 hereditary spherocytosis 191 SPTB hereditary elliptocytosis 189 hereditary spherocytosis 191 StAR 162 stature, growth hormone deficiency 164 Steinert disease (myotonic dystrophy [MD]) 23–6 stereocilin 84 Stickler syndrome 122, 125–7 strabismus, retinoblastoma 98 STRC 84 subcortical band heterotopia (SCBH) 45 supravalvular aortic stenosis (SVAS), Williams syndrome 141 supravalvular pulmonary stenosis (SVPS), Williams syndrome 141 survival of motor neurons interacting protein 179 Swiss-type agammaglobulinemia (severe combined immunodeficiency [SCID]) 205–7 tafazzin 130 TAZ (G4.5) 130 T-BOX DiGeorge/Shprintzen syndrome 134–5 Holt–Oram syndrome 136 TBX1 134–5 TBX5 135, 136 TCAP 21, 22 T-cell leukemias, ataxia–telangiectasia 2

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TCOF1 154–5 TECTA 84 tectorin 84 telethonin 21, 22 testicular feminization syndrome (androgen insensitivity syndrome [AIS]) 158–9 testosterone biosynthesis defects 159 tetrahydrobiotin (BH4) 215 TFCP2L3 84 TGIF 36, 37, 38 α-thalassemia 194–7 and mental retardation syndrome, X-linked 64–6 β-thalassemia 197–8 thanatophoric dysplasia 109, 109–10, 110 thirst, diabetes insipidus 163 thrombocytopenia Wiskott–Aldrich syndrome 207–8 X-linked 208 thymic aplasia, DiGeorge/Shprintzen syndrome 133 thyroidectomy, multiple endocrine neoplasia type 2 96 thyroid stimulating hormone (TSH) deficiency 168 titin cap 22 titin immunoglobulin domain protein 18, 20 TMCI 84 TMIE 84 TMPRSS3 84 transforming growth factor β-induced factor 38 Treacher Collins syndrome 154–5 Treacher Collins–Franceschetti syndrome 154–5 treacle (TCOF1) 154–5 triallelic inheritance, Bardet–Biedl syndrome 74 TRIM32 21, 22 trisomy 8, X-linked hydrocephalus 66 “trisomy rescue”, Angelman syndrome 31 TSC1 102–3 TSC2 102–3 TS complex (tuberous sclerosis) 101–3 TTID 18, 20 tuberin 102–3 tuberous sclerosis 101–3 tumor suppressor genes EXT1 116–7 EXT2 116–7 RB1 99–100 VHL 104–5 TWIST 151–2 UBE3A 30–1 ultrasonography, polycystic kidney disease 226 ureate levels, Lesch–Nyhan syndrome 43 uremia, polycystic kidney disease 226 USH2A 89, 90 USH3A 89, 90 usher IC 84 usherin 89, 90 Usher syndrome 87–90 USHIC nonsyndromal hearing loss 84 Usher syndrome 88–9, 89 valvular stenosis, Alagille syndrome 174 van der Woude syndrome 155–6 vaso-occlusive crisis, sickle cell anemia 193 velocardiofacial syndrome (VCFS) (DiGeorge/Shprintzen syndrome) 133–5 ventricular septal defects (VSDs) DiGeorge/Shprintzen syndrome 134 Holt–Oram syndrome 136

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laterality defects 137 Noonan syndrome 138 very-long chain fatty acids (VLCFAs) 63–4 VHL 104–5 visual disorders 69–81 Lowe syndrome 52 Pelizaeus–Merzbacher syndrome 57 visual evoked potentials (VEPs) 54 von Hippel–Lindau disease (VHL) 103–5 von Reckinghausen’s disease see neurofibromatosis type 1 von Willebrand disease 198–9 VWF 199 Waardenburg–Shah syndrome see Waardenburg syndrome Waardenburg syndrome 90–2 Hirschsprung disease 92, 177 Wagenmann–Froboese syndrome see multiple endocrine neoplasia type 2 (MEN2) WAGR syndrome (aniridia) 70–2 Walker–Warburg syndrome 46, 51 “waltzer” mice 89–90 WAS 208 Weissenbacher–Zweymuller syndrome 125–7 COL11A2 122 Pierre Robin anomaly 127 Stickler syndrome 127 Werdnig–Hoffmann disease 27–8 WFS1 84 Williams–Beuren syndrome (Williams syndrome [WS]) 141–2 Williams syndrome (WS) 141–2 Wilm’s tumor, aniridia, genitourinary anomalies mental retardation syndrome 70–2 Wilms tumor, Beckwith–Wiedemann syndrome 220–1 Wilson disease 215–6 Wiskott–Aldrich syndrome (WAS) 207–8 Wolfram syndrome 84 WS (Williams syndrome) 141–2 WT1 71 X-chromosome Alport syndrome 219 androgen insensitivity syndrome 158 Barth syndrome 130 Bruton agammaglobulinemia 202 chronic granulomatous disease 204 collagen gene disorders 122 Duchenne muscular dystrophy 4 fragile X syndrome 34 glucose-6-phosphate dehydrogenase deficiency 184 growth hormone deficiency 165 hemophilia A 186 hemophilia B 187 hereditary motor and sensory neuropathy 13 Hunter syndrome 40 juvenile retinoschisis 74 laterality defects 137 Lesch–Nyhan syndrome 43 Lowe syndrome 52 Menkes disease 212 nephrogenic diabetes insipidus 163 nonsyndromal hearing loss 84 Norrie disease 79 occipital horn syndrome 112 ornithine transcarbamylase deficiency 213 orofaciodigital syndrome type I 225 Pelizaeus–Merzbacher syndrome 58 Rett syndrome 61 severe combined immunodeficiency 206

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Wiskott–Aldrich syndrome 208 X-linked lissencephaly 48 X-linked lissencephaly with ambiguous genitalia 48 X-linked disorders adrenoleukodystrophy 62–4 agammaglobulinemia see Bruton agammaglobulinemia agenesis of the corpus callosum 67 aqueduct stenosis 66–8 α-thalassemia and mental retardation syndrome 64–6 cardiomyopathy 6 complicated spastic paraparesis 67 exudative vitreoretinopathy 79 hydrocephalus 66–8 infantile spasms 50 lissencephaly (XLIS) 45 lissencephaly with ambiguous genitalia (XLAG) 46 mental retardation 50 myoclonic epilepsy with mental retardation and 50 nuclear protein 65 retinoschisis (juvenile retinoschisis) 74–5 spastic paraplegia 58 thrombocytopenia 208 XNP 65–6 Zellweger syndrome, Leber congenital amaurosis 76 ZIC2 36, 36, 38 ZIC3 137–8 zinc finger protein 3 137–8 zinc finger protein 9 25, 26 zinc finger protein 127 59–60 ZNF9 25, 26 ZNF127 59–60

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