SECTION A
PRINCIPLES OF HUMAN GENETICS
1 The History and Impact of Genetics in
Medicine 3
Gregor Mendel and the Laws of Inheritance 3
DNA as the Basis of Inheritance 5
The Fruit Fly 6
The Origins of Medical Genetics 7
The Impact of Genetic Disease 8
Major New Developments 9
2 The Cellular and Molecular Basis of
Inheritance 13
The Cell 13
DNA: The Hereditary Material 13
Chromosome Structure 15
Types of DNA Sequence 15
Transcription 18
Translation 19
The Genetic Code 20
Regulation of Gene Expression 21
RNA-directed DNA Synthesis 22
Mutations 22
Mutations and Mutagenesis 26
3 Chromosomes and Cell Division 31
Human Chromosomes 31
Methods of Chromosome Analysis 33
Molecular Cytogenetics 34
Chromosome Nomenclature 37
Cell Division 38
Gametogenesis 41
Chromosome Abnormalities 42
4 DNA Technology and Applications 53
DNA Cloning 53
Techniques of DNA Analysis 57
5 Mapping and Identifying Genes
for Monogenic Disorders 73
Position-Independent Identification of Human Disease
Genes 73
Positional Cloning 75
The Human Genome Project 76
6 Developmental Genetics 83
Fertilization and Gastrulation 83
Developmental Gene Families 85
Role of Cilia in Developmental Abnormalities 96
The Limb as a Developmental Model 97
Developmental Genes and Cancer 100
Positional Effects and Developmental Genes 101
Hydatidiform Moles 101
Sexual Differentiation and Determination 101
Epigenetics and Development 103
Twinning 106
7 Patterns of Inheritance 109
Family Studies 109
Mendelian Inheritance 109
Multiple Alleles and Complex Traits 119
Anticipation 120
Mosaicism 120
Uniparental Disomy 121
Genomic Imprinting 121
Mitochondrial Inheritance 126
8 Population and Mathematical
Genetics 129
Allele Frequencies in Populations 129
Genetic Polymorphism 135
Segregation Analysis 135
Genetic Linkage 136
Medical and Societal Intervention 139
Conclusion 140
9 Polygenic and Multifactorial
Inheritance 143
Polygenic Inheritance and the Normal
Distribution 143
Multifactorial Inheritance-The Liability/Threshold
Model 145
Heritability 146
Identifying Genes that Cause Multifactorial
Disorders 146
Conclusion 150
SECTION B
GENETICS IN MEDICINE
10 Hemoglobin and the
Hemoglobinopathies 155
Structure of Hb 155
Developmental Expression of Hemoglobin 155
Globin Chain Structure 156
Synthesis and Control of Hemoglobin
Expression 157
Disorders of Hemoglobin 157
Clinical Variation of the Hemoglobinopathies 163
xi
xii Contents
Antenatal and Newborn Hemoglobinopathy
Screening 164
11 Biochemical Genetics 167
Inborn Errors of Metabolism 167
Disorders of Amino Acid Metabolism 167
Disorders of Branched-Chain Amino Acid
Metabolism 172
Urea Cycle Disorders 172
Disorders of Carbohydrate Metabolism 172
Disorders of Steroid Metabolism 174
Disorders of Lipid Metabolism 175
Lysosomal Storage Disorders 176
Disorders of Purine/Pyrimidine Metabolism 178
Disorders of Porphyrin Metabolism 179
Organic-Acid Disorders 180
Disorders of Copper Metabolism 180
Peroxisomal Disorders 180
Disorders Affecting Mitochondrial Function 181
Prenatal Diagnosis of Inborn Errors
of Metabolism 183
12 Pharmacogenetics 185
Definition 185
Drug Metabolism 185
Genetic Variations Revealed by the Effects of
Drugs 186
Pharmacogenetics 188
13 Immunogenetics 193
Immunity 193
Innate Immunity 193
Specific Acquired Immunity 195
Inherited Immunodeficiency Disorders 201
Blood Groups 204
14 Cancer Genetics 209
Differentiation between Genetic and Environmental
Factors in Cancer 209
Oncogenes 211
Tumor Suppressor Genes 214
Epigenetics and Cancer 218
Genetics of Common Cancers 219
Genetic Counseling in Familial Cancer 225
15 Genetic Factors in Common Diseases 233
Genetic Susceptibility to Common Disease 233
Types and Mechanisms of Genetic Susceptibility 233
Approaches to Demonstrating Genetic Susceptibility
to Common Diseases 233
Disease Models for Multifactorial Inheritance 235
Type 1 Diabetes 237
Type 2 Diabetes 238
Crohn Disease 238
Hypertension 239
Coronary Artery Disease 240
Schizophrenia 242
Alzheimer Disease 243
Hemochromatosis 244
Venous Thrombosis 244
Age-Related Macular Degeneration 245
SECTION C
CLINICAL GENETICS
16 Congenital Abnormalities and Dysmorphic
Syndromes 249
Incidence 249
Definition and Classification of Birth Defects 250
Genetic Causes of Malformations 254
Environmental Agents (Teratogens) 259
Malformations of Unknown Cause 262
Counseling 263
17 Genetic Counseling 265
Definition 265
Establishing the Diagnosis 265
Calculating and Presenting the Risk 266
Discussing the Options 267
Communication and Support 267
Genetic Counseling-Directive
or Non-Directive? 268
Outcomes in Genetic Counseling 268
Special Problems in Genetic Counseling 269
18 Chromosome Disorders 273
Incidence of Chromosome Abnormalities 273
Disorders of the Sex Chromosomes 276
Chromosome Deletion and Microdeletion
Syndromes 280
Disorders of Sexual Differentiation 287
Chromosomal Breakage Syndromes 288
Xeroderma Pigmentosa 289
Indications for Chromosomal/Microarray-CGH
Analysis 289
19 Single-Gene Disorders 293
Huntington Disease 293
Myotonic Dystrophy 295
Hereditary Motor and Sensory Neuropathy 296
Neurofibromatosis 298
Marfan Syndrome 300
Cystic Fibrosis 301
Inherited Cardiac Arrhythmias and
Cardiomyopathies 304
Spinal Muscular Atrophy 306
Duchenne Muscular Dystrophy 307
Prospects for Treatment 308
Hemophilia 309
20 Screening for Genetic Disease 313
Screening Those at High Risk 313
Carrier Testing for Autosomal Recessive and X-Linked
Disorders 313
Contents xiii
Presymptomatic Diagnosis of Autosomal Dominant
Disorders 316
Ethical Considerations in Carrier Detection
and Predictive Testing 317
Population Screening 318
Criteria for a Screening Program 318
Neonatal Screening 319
Population Carrier Screening 321
Genetic Registers 322
21 Prenatal Testing and Reproductive
Genetics 325
Techniques Used in Prenatal Diagnosis 325
Prenatal Screening 328
Indications for Prenatal Diagnosis 331
Special Problems in Prenatal Diagnosis 333
Termination of Pregnancy 335
Preimplantation Genetic Diagnosis 335
Assisted Conception and Implications
for Genetic Disease 336
Non-Invasive Prenatal Diagnosis 337
Prenatal Treatment 338
22 Risk Calculation 339
Probability Theory 339
Autosomal Dominant Inheritance 340
Autosomal Recessive Inheritance 342
Sex-Linked Recessive Inheritance 343
The Use of Linked Markers 345
Bayes' Theorem and Prenatal Screening 345
Empiric Risks 346
23 Treatment of Genetic Disease 349
Conventional Approaches to Treatment
of Genetic Disease 349
Therapeutic Applications of Recombinant DNA
Technology 350
Gene Therapy 350
RNA Modification 354
Targeted Gene Correction 355
Stem Cell Therapy 356
24 Ethical and Legal Issues in Medical
Genetics 361
General Principles 361
Ethical Dilemmas in the Genetic Clinic 363
Ethical Dilemmas and
the Public Interest 366
Conclusion 370
APPENDIX: Websites and Clinical Databases 372
Glossary 374
Multiple-Choice Questions 389
Case-Based Questions 400
Multiple-Choice Answers 405
Case-Based Answers 418
