Emery's Elements of Medical Genetics

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