Essential Medical Genetics

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