Adopted at Cambridge University

Essential Medical Genetics provides students, clinicians, counsellors and scientists with the up-to-date information they need regarding the basic principles underlying medical genetics. It also provides guidance on how to apply current knowledge in clinical contexts, covering a wide variety of topics: from genome structure and function to mutations, screening and risk assessment for inherited disorders.

This sixth edition has been substantially updated to include, for instance, the latest information on the Human Genome Project as well as several new molecular genetic and chromosome analysis techniques. In full colour throughout, it includes a number of brand new features, including: a large number of self-assessment questions; 'Essentials' chapter summaries; further reading suggestions; and case study scenarios introducing clinical situations. An invaluable new section gives illustrated practical advice regarding how to choose the best available online genetic databases and also, importantly, how to most easily and most efficiently use them, for a wide range of purposes.

Essential Medical Genetics is the perfect resource for a course on medical genetics, and is now accompanied by a regularly updated website and the FREE enhanced Wiley Desktop Edition (upon purchase of the book).

The companion website atwww.wiley.com/go/tobias features figures from the book in PowerPoint format and a link to the authors' website with regularly updated links to genetic databases and additional self-test questions.

This title is also available as a mobile App from MedHand Mobile Libraries. Buy it now from iTunes,Google Play or theMedHand Store.

Edward S. Tobias, Professor of Genetic Medicine, University of Glasgow, and Honorary Consultant in Medical Genetics, West of Scotland Regional Genetics Service, Institute of Medical Genetics, Glasgow. Medical Genetics undergraduate Teaching Lead, Clinical Director, MSc in Medical Genetics, and Fellow of the Higher Education Authority.

Dr Tobias won the Best College Teacher Award at Glasgow University in March 2013, as chosen by the Student Representative Council and the students themselves. He also won the Teaching Excellence Award 2012 from the University's Principal and Senate Committee. Glasgow University came top in the UK National Student Survey 2012 for Genetics teaching. Michael Connor, Professor of Medical Genetics, University of Glasgow, and Director of the West of Scotland Regional Genetics Service, Institute of Medical Genetics, Yorkhill, Glasgow

Malcolm Ferguson-Smith, Emeritus Professor of Pathology, University of Cambridge and formerly Director of the East Anglia Regional Genetics Service, Addenbrooke's Hospital, Cambridge

Preface vii

Acknowledgements ix

How to get the best out of your textbook x

Part 1: Basic principles 1

1 Medical genetics in perspective 3

Scientific basis of medical genetics 5

Clinical applications of medical genetics 9

2 The human genome 13

Structure and organisation of the genome 14

Gene identification 14

Th e Human Genome Project 14

3 Nucleic acid structure and function 23

Nucleic acid structure 24

Nucleic acid function 26

Gene regulation 29

DNA replication 31

Mutation types, eff ects and nomenclature 32

4 DNA analysis 41

Basic methods 42

Mutation detection 43

Indirect mutant gene tracking 52

Analysis of DNA length polymorphisms 53

Analysis of single-nucleotide polymorphisms 54

5 Chromosomes 57

Chromosome structure 58

Chromosome analysis 59

Chromosome heteromorphisms 65

Chromosomes in other species 66

Mitochondrial chromosomes 68

Mitosis 69

6 Gametogenesis 73

Meiosis 74

Spermatogenesis 76

Oogenesis 78

Fertilisation 78

X-inactivation and dosage compensation 79

Sex chromosome aberrations 80

Sex determination and differentiation 83

Genomic imprinting (parental imprinting) 83

7 Chromosome aberrations 89

Numerical aberrations 90

Structural aberrations 92

Cytogenetic and molecular methods for the detection of chromosomal aberrations 100

Identification of the chromosomal origin of complex structural rearrangements 107

Other aberrations 111

8 Typical Mendelian inheritance 117

Introduction to autosomal single-gene inheritance 118

Autosomal dominant inheritance 118

Autosomal recessive inheritance 120

Introduction to sex-linked inheritance 123

X-linked recessive inheritance 125

X-linked dominant inheritance 127

Y-linked inheritance (holandric inheritance) 128

9 Atypical Mendelian inheritance 131

Genetic anticipation 132

Pseudoautosomal inheritance 134

Autosomal dominant inheritance with sex limitation 134

Pseudodominant inheritance 134

X-linked dominant inheritance with male lethality 135

Mosaicism 135

Modifi er genes and digenic inheritance 135

Uniparental disomy 136

Imprinting disorders 136

10 Non-Mendelian inheritance 141

Multifactorial disorders 142

Somatic cell genetic disorders 147

Mitochondrial disorders 147

11 Medical genetics in populations 151

Selection for single-gene disorders 152

Founder effect and genetic drift for single-gene disorders 153

Altered mutation rate for single-gene disorders 154

Linkage analysis and the International Hapmap Project 154

Human population evolution and migration 155

Part 2: Clinical applications 161

12 Genetic assessment, genetic counselling and reproductive options 163

Communication of advice 164

Special points in counselling 168

Prenatal diagnosis 170

Amniocentesis 170

Chorionic villus sampling 174

Cordocentesis, fetal skin biopsy and fetal liver biopsy 175

Ultrasonography 175

Fetal cells in the maternal circulation 175

Free fetal DNA and RNA detection 175

Preimplantation genetic diagnosis 176

13 Family history of cancer 179

General principles 180

Tumour suppressor genes 181

Genes involved in DNA repair mechanisms 187

Oncogenes 187

Other cancer-related genes 189

Genetic counselling aspects of cancer 189

Common familial cancer predisposition syndromes 189

14 Family history of common adult-onset disorder 199

General principles 200

Diabetes mellitus: common and monogenic forms 200

Dementia: Alzheimer disease, Huntington disease, prion diseases and other causes 202

15 Strong family history typical Mendelian disease 209

Cystic fibrosis 210

Duchenne and Becker muscular dystrophies 212

Neurofi bromatosis type 1 214

16 Strong family history other inheritance mechanisms 219

Myotonic dystrophy 220

Fragile X syndrome 221

Mitochondrial disorder 222

Imprinting-related disorder 223

Chromosomal translocation 224

17 Screening for disease and for carriers 229

Prenatal screening 230

Neonatal screening 233

Carrier detection in the adult population 234

Presymptomatic screening of adults 237

18 Family history of one or more congenital malformations 241

Aetiology 242

Chromosomal disorders 243

Neural tube defects 247

Teratogenic eff ects 250

Multiple malformation syndromes 253

Part 3: Electronic databases a user's guide 265

19 Electronic databases a user's guide 267

Finding information regarding specifi c conditions and names of associated genes 268

Laboratories undertaking genetic testing 270

Patient information and support groups 270

Gene- and protein-specifi c sequence, structure, function and expression information 272

Nucleotide sequences and human mutations 281

Automatic primer design tools 281

Displaying map data for genes and markers 287

Online missense mutation analysis tools 288

Computer-aided syndrome diagnosis 293

Professional genetics societies 297

Th e Human Genome Project: ethics and education 297

Self-assessment answers 305

Appendix 1: Odds, probabilities and applications of Bayes theorem 312

Appendix 2: Calculation of the coeffi cients of relationship and inbreeding 314

Appendix 3: Population genetics of single-gene disorders 315

Appendix 4: Legal aspects 317

Glossary 318

Index 324