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

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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

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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