Clinical Cardiogenetics (eBook)

Clinical Cardiogenetics 2
Preface 4
Contents 6
Contributors 9
Abbreviations 13
Part I:Genetics 14
1: Introduction to Molecular Genetics 15
1.1 Introduction 15
1.1.1 DNA, What Is It, Where Is It, and How Are Proteins Made? 15
1.1.1.1 Genotyping in Mendelian and Non-Mendelian Disorders 20
1.1.1.2 Genetic Heterogeneity of Monogenic Disorders 23
1.1.1.3 DNA-Diagnostics: Basic Strategies 24
1.1.1.4 Indirect DNA-Diagnostics: Linkage Analysis and Risk Haplotype Analysis 27
1.1.1.5 Direct DNA-Diagnostics: Screening for Small Mutations 28
Sanger Sequencing 28
Gene Scanning Methods: Alternatives to Sequencing Entire Candidate Genes 28
New Technologies Emerging on the Horizon 29
References 31
2: Clinical Genetics 32
2.1 Introduction 32
2.1.1 The Clinical Genetic Intake 33
2.1.1.1 Family History 33
2.1.2 Pedigree Construction 33
2.1.3 Basic Concepts in Inherited Disease 34
2.1.4 Mitosis and Meiosis 36
2.1.4.1 Chromosomal Abnormalities 37
2.1.4.2 Inheritance Patterns 38
2.1.5 Single Gene Disorders: Mendelian Inheritance 38
2.1.5.1 Autosomal Dominant Inheritance 39
2.1.5.2 Autosomal Recessive Inheritance 39
2.1.5.3 X-Linked Recessive Inheritance 39
2.1.5.4 X-Linked Dominant Inheritance 40
2.1.6 Non-Mendelian Inheritance 41
2.1.6.1 Multifactorial Inheritance 41
2.1.6.2 Maternal (Mitochondrial) Inheritance 42
2.1.7 New (De Novo) Mutations 43
2.1.8 Mosaicism 44
2.1.9 On Penetrance and Variable Expressivity 44
2.2 Genotype–Phenotype Correlations 45
2.3 Basic Concepts in Population Genetics 45
2.3.1 Hardy–Weinberg Equilibrium 45
2.3.2 Mutation–Selection Equilibrium 46
2.4 Founder Mutations 46
2.5 Genetic Isolates 46
2.5.1 Consanguinity 46
2.5.2 Genetic Testing 47
2.5.3 Genetic Counseling 47
2.6 Predictive Testing and the Dynamics of Family Studies 49
2.6.1 Predictive DNA Testing 49
2.6.2 Adverse Consequences of Predictive Testing 50
2.6.3 Predictive Testing in Minors 50
2.6.3.1 Conducting Family Studies 51
2.6.4 Contacting Family Members 51
2.6.5 Prenatal Diagnosis 52
2.6.6 Population Genetic Screening Issues 52
2.6.7 Interpreting Genetic Test Results 53
2.6.8 The Cardiogenetics Outclinic 54
References 54
Part II:Cardiomyopathy 56
3: Hypertrophic Cardiomyopathy 57
3.1 Introduction 57
3.2 Prevalence and Diagnosis 57
3.3 Pathophysiology and Natural History 57
3.4 Disease Penetrance 61
3.5 Therapy 62
3.6 Sudden Cardiac Death and Risk Stratification 63
3.7 Genetics of HCM 64
3.8 Screening of Relatives: Genetic Counseling and Testing 66
3.9 Summary 67
References 67
4: Familial Dilated Cardiomyopathy 72
4.1 Introduction 72
4.2 Epidemiology and Prevalence 72
4.2.1 Diagnosis and Clinical Course of Familial DCM 73
4.2.2 Genetic Background 73
4.2.3 Genes and Mutations in DCM 75
4.3 Molecular Pathophysiology 77
4.3.1 Sarcomere Proteins 77
4.3.1.1 Actin 77
4.3.1.2 Metavincullin 78
4.3.1.3 Telethonin 78
4.3.1.4 Troponin-T 78
4.3.1.5 Troponin-I 78
4.3.1.6 Troponin C 78
4.3.1.7 Tropomyosin 78
4.3.1.8 Beta-Myosin Heavy Chain 78
4.3.1.9 Titin 79
4.3.2 Nuclear Envelope Proteins 79
4.3.2.1 Lamin A/C 79
4.3.2.2 Thymopoietin 79
4.3.3 Cytoskeletal Proteins 79
4.3.3.1 Desmin 79
4.3.3.2 Dystrophin 80
4.3.3.3 Sarcoglycans and Dystrophin-Associated Glycoproteins 80
4.3.4 Mitochondrial DNA Mutations 81
4.3.4.1 Genes Involved in Electrolyte Homeostasis 81
SCN5A 81
Phospholamban 81
4.3.5 Cardiac ATP-Sensitive Potassium Channels 81
4.3.6 DCM and Ventricular Noncompaction Cardiomyopathy 81
4.4 Therapy 82
4.5 Prognosis and Risk Stratification 82
4.6 Family Screening 83
4.7 Summary 83
References 85
5: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 87
5.1 Introduction 87
5.2 Molecular and Genetic Background 88
5.2.1 Desmosome Function 88
5.2.2 Desmosomal Dysfunction and ARVD/C Pathophysiology 89
5.2.3 Desmosomal Disease 89
5.2.4 Autosomal Recessive Disease 90
5.2.5 Autosomal Dominant Disease 90
5.2.6 Other, Nondesmosomal, Genes 91
5.3 Epidemiology 92
5.4 Clinical Presentation 92
5.5 Clinical Diagnosis 93
5.6 ECG Criteria 93
5.6.1 Depolarization Abnormalities 93
5.6.2 Repolarization Abnormalities 95
5.6.3 Arrhythmias 95
5.6.4 Global and/or Regional Dysfunction and Structural Alterations 95
5.6.5 Endomyocardial Biopsy 96
5.6.6 Family History 96
5.6.7 Discussion on Diagnostic Criteria 96
5.6.8 Modifications for Family Members 97
5.6.9 Nonclassical ARVD/C Subtypes 98
5.6.9.1 Naxos Disease 98
5.6.9.2 Carvajal Syndrome 98
5.6.9.3 Left Dominant ARVD/C (LDAC) 98
5.7 Differential Diagnosis 98
5.8 Molecular Genetic Analysis 99
5.9 Prognosis and Therapy 99
5.10 Summary 101
References 101
6: Noncompaction Cardiomyopathy 105
6.1 Introduction 105
6.1.1 Definition 106
6.1.2 Pathology 107
6.1.2.1 Macroscopy 107
6.1.2.2 Microscopy 109
6.2 Epidemiology 110
6.3 Etiology and Molecular Genetics 110
6.3.1 Molecular defects in NCCM 110
6.4 Pathogenesis 112
6.4.1 Isolated NCCM 112
6.4.2 Nonisolated NCCM 113
6.4.3 Congenital heart disease 113
6.4.4 Neuromuscular Disease 115
6.4.5 Syndromes 116
6.4.6 Mitochondrial 116
6.4.7 Miscellaneous 119
6.5 Clinical Aspects 119
6.6 Differential diagnosis 120
6.7 Therapy, follow-up, and prognosis 121
6.7.1 Therapy and follow-up 121
6.7.2 Prognosis 121
6.8 Risk stratification and indication for ICD 121
6.9 Cardiogenetic aspects 122
6.9.1 Molecular and cardiologic family screening 122
6.9.2 Genotype–phenotype correlations 122
6.9.3 Molecular strategies 122
6.10 Summary 123
References 124
7: Mitochondrial Cardiomyopathy 131
7.1 Introduction 131
7.2 MELAS Syndrome 133
7.3 Kearns–Sayre Syndrome 134
7.4 Conclusion 135
References 135
8: Restrictive Cardiomyopathy 137
8.1 Introduction 137
8.2 Molecular Background 137
8.3 Clinical Aspects 139
8.4 Diagnosis 139
8.5 Clinical Approach and Differential Diagnosis 140
8.6 Treatment 140
8.7 Prognosis 140
8.8 Idiopatic and Familial Restrictive Cardiomyopathy 140
8.9 Restrictive Cardiomyopathy as Part of Specific Clinical Conditions with Known or Suspected Genetic Background (Selected Sub 141
8.9.1 Non-infiltrative Restrictive Cardiomyopathy 141
8.9.1.1 Scleroderma/Systemic sclerosis (SSc) 141
8.9.1.2 Pseudoxanthoma Elasticum 142
8.9.1.3 Diabetic Cardiomyopathy 142
8.9.2 Infiltrative 142
8.9.2.1 Cardiac Amyloidosis 142
8.9.2.2 Sarcoidosis 143
8.9.2.3 Gaucher disease 143
8.9.2.4 Mucopolysaccharidoses: Hurler Disease, Hunter disease 143
8.9.3 Storage Diseases 144
8.9.3.1 Hemochromatosis 144
8.9.3.2 Fabry Disease 144
8.9.3.3 Glycogen Storage Disease 145
8.9.4 Endomyocardial Causes of Restrictive Cardiomyopathy 145
8.9.4.1 Endomyocardial Fibrosis 145
8.9.4.2 Hypereosinophylic Syndrome 145
8.10 Summary 146
References 146
Part III:Primary Electrical Heart Diseases 148
9: Congenital Long QT-Syndrome 149
9.1 Introduction 149
9.2 Electrophysiological and Molecular Mechanisms 149
9.2.1 Cardiac Action Potential 149
9.2.2 Cardiac Ion Channels 151
9.3 Epidemiology and Prevalence 152
9.4 Molecular Genetics and Pathogenesis 152
9.4.1 Molecular Genetics 152
9.4.2 Mechanisms Involved in Arrhythmia 153
9.5 Clinical Aspects 154
9.5.1 Clinical Presentation in General 154
9.5.2 Genotype–Phenotype Specific Correlations 154
9.5.3 Clinical Diagnosis 155
9.5.4 Clinical Diagnostic Criteria 156
9.5.5 QT-Interval 156
9.5.6 T Wave Morphology 157
9.5.7 T Wave Alternans 159
9.5.8 QT-Dispersion 159
9.5.9 Sinus Node Dysfunction 159
9.5.10 Holter Monitoring 159
9.5.11 Exercise Testing 159
9.5.12 Epinephrine Stress Test 159
9.5.13 Differential Diagnosis 160
9.6 Molecular Genetic Diagnosis 160
9.7 Risk Stratification 161
9.7.1 Gender 161
9.7.2 QTc Duration 161
9.7.3 Time-Dependent Syncope 161
9.7.4 Stratification of Risk 162
9.8 Specific Risk Factors 162
9.8.1 Biophysical Function and Location of the Mutation 162
9.8.2 LQTS Genotypes 162
9.8.3 Postpartum Period 162
9.8.4 Family History 163
9.9 Therapy and Prognosis 163
9.9.1 Symptomatic Patients 163
9.9.1.1 General Lifestyle Measures 163
9.9.1.2 Beta-Adrenergic Blockade 164
9.9.1.3 Left Cardiac Sympathetic Denervation 164
9.9.1.4 Pacemaker Therapy 164
9.9.1.5 Implantable Cardioverter Defibrillator 164
9.9.1.6 Genotype Specific Measures and Therapies 165
9.9.2 Asymptomatic Patients 166
9.10 Family Screening 166
9.11 Summary 167
References 167
10: The Brugada Syndrome 171
10.1 Introduction 171
10.2 Definition and Epidemiology 171
10.3 Genetics of the Brugada Syndrome 172
10.4 Pathophysiology: Cellular and Ionic Mechanisms 174
10.5 Clinical Manifestations of the Brugada Syndrome 175
10.6 Diagnosis 179
10.6.1 ECG Findings 179
10.6.2 Differential Diagnosis and ECG Modulators 180
10.6.3 Diagnostic Tools: Pharmacological Tests and Upper Right Precordial Leads 181
10.7 Prognosis and Risk Stratification 183
10.8 Treatment 185
10.8.1 Implantable Cardioverter Defibrillator 185
10.8.2 Pharmacological Options 186
10.9 Cardiogenetics Aspects 187
10.9.1 Genetic Diagnosis and Genotype–Phenotype Correlation 187
10.9.2 Family Screening 188
10.10 Summary 190
References 190
11: Short QT Syndrome 194
11.1 Introduction 194
11.2 Molecular and Genetic Background 194
11.3 Epidemiology and Prevalence 195
11.4 Pathophysiology 195
11.5 Clinical Aspects and Clinical Diagnosis 196
11.5.1 Clinical Presentation 196
11.6 Diagnosis of Short QT Syndrome 197
11.7 Differential Diagnosis 198
11.8 Therapy, Follow-up, and Prognosis 198
11.8.1 Pharmacologic Therapy of Short QT Syndrome 198
11.8.2 ICD Therapy 199
11.9 Risk Stratification and Indication for ICD 199
11.10 Cardiogenetics Aspects 200
11.11 Summary 200
References 200
12: Catecholaminergic Polymorphic Ventricular Tachycardia 202
12.1 Introduction 202
12.2 Etiology 202
12.2.1 Molecular Background 202
12.2.2 Pathophysiology 203
12.3 Clinical Aspects 203
12.3.1 Epidemiology 203
12.3.2 Clinical Diagnosis 204
12.4 Genetic Diagnosis 204
12.4.1 Differential Diagnosis 206
12.4.2 Therapy and Prognosis 207
12.4.2.1 Lifestyle Modifications 207
12.4.2.2 b-Blocker Therapy 207
12.4.2.3 Other Pharmacologic Therapy 207
12.4.2.4 Nonpharmacologic Therapy 208
12.4.3 Follow-up 208
12.4.4 Risk Stratification/Indication for ICD 208
12.4.5 Cardiogenetics Aspects 208
12.5 Summary 209
References 209
13: A Molecular Genetic Perspective on Atrial Fibrillation 212
13.1 Introduction 212
13.2 Epidemiology 212
13.3 Molecular Background 213
13.4 Pathophysiology 215
13.5 Molecular Genetics 216
13.6 Potassium Channels: Gain-Of-Function Mutations 217
13.6.1 KCNQ1 217
13.6.2 KCNE2 and KCNJ2 218
13.7 Potassium Channels: Loss-of-Function Mutations 219
13.7.1 KCNA5 219
13.8 A Potassium Channel Variant and “Secondary Hit” Hypothesis 219
13.9 Are Potassium Channel Mutations Common? 220
13.10 Connexins 220
13.11 Sodium Channels: Loss-of-Function Mutations 221
13.12 Sodium Channels: Gain-of-Function Mutations 222
13.13 Atrial Natriuretic Peptide 223
13.14 Unknown Loci 223
13.15 Genome Wide Association Studies 223
13.16 Other Gene Associations 224
13.16.1 ACE 224
13.16.2 GNB3, Enos, MMP-2, IL-10 224
13.17 The Autonomic Nervous System 224
13.18 Clinical Aspects – Genetic Diagnosis and Targeted Therapy 225
13.19 Summary 227
References 227
Part IV:Other Hereditary Arrythmias 231
14: Idiopathic Ventricular Fibrillation 232
14.1 Introduction 232
14.2 Clinical Diagnosis 233
14.3 Historical Diagnoses 234
14.4 Genetic Diagnosis 235
14.5 Therapy, Follow-up and Prognosis 236
14.6 Conclusions 238
References 239
15: The Genetics of Mitral Valve Prolapse 242
15.1 Introduction 242
15.2 Epidemiology and Definitions 242
15.3 Pathophysiology and Clinical Aspects of Mitral Valve Disease 242
15.4 Genetic Aspects of Mitral Valve Disease 244
15.5 Summary and Conclusions 244
References 244
16: Atrioventricular (AV) Reentry Tachycardia 246
16.1 Introduction 246
16.2 Epidemiology in AVRT 246
16.2.1 Wolff–Parkinson–White Syndrome 246
16.2.2 Mahaim Tachycardia 247
16.2.3 Concealed Bypasses 247
16.3 Pathogenesis in AVRT 247
16.3.1 Accessory Pathways (APs) 247
16.3.2 Arrhythmia Mechanisms in AVRT 248
16.4 Clinical Aspects 249
16.4.1 AVRT in General 249
16.4.1.1 WPW Syndrome 249
16.5 Electrocardiographic Diagnosis 250
16.5.1 WPW Syndrome 250
16.5.2 Mahaim Tachycardia 250
16.6 Treatment 250
16.7 Genetics in AVRT 251
16.7.1 WPW Syndrome 251
16.7.1.1 Genes 251
16.7.1.2 Animal Models for WPW Syndrome 252
16.7.2 Genetics in Mahaim Tachycardia 252
16.8 Summary 252
References 253
17: Hereditary Cardiac Conduction Diseases 256
17.1 Introduction 256
17.2 First Description of Cardiac Conduction Defect 256
17.3 Cardiac Conduction Defect is a Genetic Disease 257
17.3.1 Clinical and Molecular Description of Progressive Familial Conduction Defects 257
17.3.1.1 Transient Receptor Potential Cation Channel, Subfamily M, Member 4 Gene (TRPM4) Associated with Familial Conduction Di 257
17.3.1.2 Sodium Channel Alpha Subunit Associated with Lenègre Disease 258
17.3.1.3 SCN5A Overlap Syndrome 259
17.3.1.4 Sodium Channel beta1 Subunit Mutations Associated with Cardiac Conduction Disease 259
17.3.2 Clinical and Molecular Description of Lamin A/C Mutations in Dilated Cardiomyopathies Associated with Conduction Defects 260
17.3.3 Clinical and Molecular Description of Secundum Atrial Septal Defects Associated with Atrioventricular Conduction Defects 260
17.3.4 Molecular Screening in Cardiac Conduction Defects 261
17.3.5 Conclusions 261
References 261
Part V:Other Hereditary Cardiac Diseases and Conditions 264
18: Connective Tissue Disorders and Smooth Muscle Disorders in Cardiology 265
18.1 Introduction 265
18.2 Marfan Syndrome 265
18.2.1 Etiology 266
18.2.1.1 Molecular Genetics 266
18.2.1.2 Pathophysiology 266
18.2.2 Clinical Aspects 267
18.2.2.1 Skeletal System 267
18.2.2.2 Cardiovascular System 269
18.2.2.3 Ocular System 270
18.2.2.4 Pulmonary System 271
18.2.2.5 Dural Sac 271
18.2.2.6 Skin and Integuments 271
18.2.2.7 Other 271
18.2.3 Genetic Diagnosis 271
18.2.4 Genotype–Phenotype Correlation 272
18.2.5 Differential Diagnosis 272
18.2.6 Therapy/Follow-up/Prognosis 274
18.2.6.1 Cardiovascular Management 274
18.2.6.2 Surgical Treatment 274
18.2.6.3 Management of Other Manifestations 275
18.2.6.4 Pregnancy 275
18.2.6.5 New Developments in Treatment of Marfan Syndrome 275
18.3 Loeys–Dietz Syndrome 276
18.3.1 Molecular Background 276
18.3.2 Differential Diagnosis 276
18.3.3 Treatment 277
18.4 Ehlers–Danlos Syndrome, Vascular Type 277
18.5 Arterial Tortuosity Syndrome 278
18.6 Nonsyndromic Aortic Aneurysms and Dissections 279
18.6.1 Management 280
18.7 Other Connective Tissue Disorders 280
18.8 Summary 281
References 282
19: Genetics of Congenital Heart Defects 285
19.1 Introduction 285
19.2 Congenital Heart Defects and Monogenic Disease 287
19.3 Complex Role of Genes in Congenital Heart Defects 287
19.4 Isolated Congenital Heart Defects 289
19.4.1 Bicuspid Aortic Valves 289
19.4.2 Atrial Septal Defect (Type Secundum) 290
19.4.3 Atrioventricular Septal Defect 291
19.5 Congenital Heart Defects Associated with Syndromes 291
19.5.1 Down Syndrome/Trisomy 21 294
19.5.2 Turner (Ullrich-Turner) Syndrome 294
19.5.3 Noonan Syndrome 295
19.5.4 Digeorge Syndrome/Velocardiofacial Syndrome/22q11 Deletion 295
19.5.5 Holt-Oram 297
19.5.6 CHARGE Syndrome 297
19.6 Williams (Williams-Beuren) Syndrome 297
19.7 Summary and Future Research Projects 298
References 300
20: Genetic Disorders of the Lipoprotein Metabolism Diagnosis and Management307
20.1 Introduction 307
20.2 Structure of Lipids and Lipoproteins 308
20.3 Lipid and Lipoprotein Metabolism 308
20.3.1 Absorption of Exogenous and Endogenous Lipids 308
20.3.2 Endogenous Synthesis of Lipids and Lipoproteins 310
20.3.3 HDL Metabolism and Reverse Cholesterol Transport 310
20.4 Genetic Causes of Elevated LDL-C Levels 311
20.4.1 Familial Hypercholesterolemia 312
20.4.1.1 Genetics 312
20.4.1.2 Clinical Characteristics 312
20.4.1.3 Diagnosis 312
20.4.1.4 Management 313
20.4.2 Familial Defective Apolipoprotein B 315
20.4.2.1 Genetics 315
20.4.2.2 Clinical Characteristics, Diagnosis, and Management 315
20.4.3 Autosomal Recessive Hypercholesterolemia 315
20.4.3.1 Genetics 315
20.4.3.2 Clinical Characteristics 315
20.4.3.3 Diagnosis 316
20.4.3.4 Management 316
20.4.4 Familial Combined Hyperlipidemia 316
20.4.4.1 Genetics 316
20.4.4.2 Clinical Characteristics 316
20.4.4.3 Diagnosis 316
20.4.4.4 Management 316
20.4.5 Sitosterolemia 317
20.4.5.1 Genetics 317
20.4.5.2 Clinical Characteristics 317
20.4.5.3 Diagnosis 317
20.4.5.4 Management 317
20.5 Genetic Causes of HDL-C Disorders 317
20.5.1 Apolipoprotein AI Deficiency 318
20.5.1.1 Genetics 319
20.5.1.2 Clinical Characteristics 319
20.5.1.3 Diagnosis 319
20.5.1.4 Management 319
20.5.2 ABCA1 Deficiency and Tangier Disease 320
20.5.2.1 Genetics 320
20.5.2.2 Clinical Characteristics 320
20.5.2.3 Diagnosis 321
20.5.2.4 Management 321
20.5.3 Familial LCAT Deficiency and Fish Eye Disease 321
20.5.3.1 Genetics 321
20.5.3.2 Clinical Characteristics 321
20.5.3.3 Diagnosis 322
20.5.3.4 Management 322
20.5.4 Genetic Disorders of CETP 322
20.5.4.1 Genetics 322
20.5.4.2 Clinical Characteristics 322
20.6 Genetic Causes of Elevated Triglycerides 323
20.6.1 LPL-Deficiency and Apo-CII Deficiency 324
20.6.1.1 Genetics 324
20.6.1.2 Clinical Characteristics 324
20.6.1.3 Diagnosis 324
20.6.1.4 Treatment 324
20.6.2 Familial Dysbetalipoproteinemia (Apo E2/E2 Deficiency) 324
20.6.2.1 Genetics 325
20.6.2.2 Clinical Characteristics 325
20.6.2.3 Diagnosis 325
20.6.2.4 Management 325
20.6.3 Familial Combined Hyperlipidemia 325
20.6.4 Familial Hypertriglyceridemia 325
20.6.4.1 Clinical Characteristics 325
20.6.4.2 Diagnosis 326
20.6.4.3 Management 326
20.7 Future Candidates 326
20.8 Summary 326
References 327
21: Novel Insights into Genetics of Arterial Thrombosis 333
21.1 Introduction 333
21.2 Hemostatic System 334
21.3 Platelet-Membrane Glycoproteins and Von Willebrand Factor Gene Polymorphisms 337
21.3.1 Platelet Receptors 337
21.3.2 Von Willebrand Factor 338
21.4 Coagulation Gene Polymorphisms 339
21.4.1 Initiation of the Extrinsic Pathway of Coagulation 339
21.4.1.1 Factor VII 339
21.4.1.2 Tissue Factor 340
21.4.2 Contact Activation and the Intrinsic Pathway of Coagulation 340
21.4.2.1 Factor XII 340
21.4.2.2 Factor XI, Factor IX, and Factor VIII 340
21.4.3 Common Coagulation Pathway 341
21.4.3.1 Factor V and Prothrombin 341
21.4.4 Protein C Pathway 341
21.4.5 Fibrinogen and Factor XIII 342
21.4.5.1 Fibrinogen 342
21.4.5.2 Factor XIII 343
21.5 Fibrinolytic System 343
21.5.1 Fibrinolysis 343
21.5.2 Fibrinolytic Inhibitors 344
21.6 Conclusions 345
21.7 Clinical Relevance 346
References 347
22: The Pharmacogenetics of Atherosclerosis 354
22.1 Introduction 354
22.2 Pharmacogenetics: Tailored Therapy to Fit Individual Profiles 354
22.3 Thiopurine Methyltransferase 357
22.4 The Cytochrome P450 357
22.5 Prediction of Efficacy in the Treatment of Atherosclerosis 357
22.6 Lipoprotein Lipase 357
22.7 HMG-CoA-Reductase Gene 358
22.8 PCSK9 359
22.9 Cholesterylesther Transfer Protein 359
22.10 Apolipoprotein E 360
22.11 Adverse Drug Reactions 361
22.12 ACE Insertion/Deletion Polymorphism 361
22.13 Future Expectations 363
22.14 Pharmacogenetics and Current Practice 363
22.15 The Pharmaceutical Industry’s View 364
22.16 The Geneticist’s View 364
22.17 The Clinician’s View 365
22.18 Summary 366
References 366
23: Genetics of (Premature) Coronary Artery Disease 369
23.1 Introduction 369
23.2 Importance of Family History 369
23.2.1 Familial Forms of Coronary Artery Disease 371
23.2.2 MEF2A 371
23.2.3 LRP6 371
23.3 Heritability Estimates of Coronary Artery Disease 372
23.4 Heritability of Coronary Anatomy and Pathology 372
23.5 Genes Affecting Coronary Artery Disease 372
23.6 Genome-Wide Association Studies for CAD and MI – Novel Insights 373
23.7 Chromosome 9p21.3 373
23.7.1 Pleiotropic Effects of Chromosome 9p21.3 373
23.7.2 Pathophysiology behind Chromosome 9p21.3 374
23.8 Chromosome 1p13.3 – Genetic Elevation of LDL Levels Translates to Risk of CAD/MI 375
23.9 Chromosome 1q41 – Link to Collagen Processing 376
23.10 Chromosome 10q11.21 – Link to EPC Recruitment and Inflammation 376
23.11 Chromosome 2q33 – Link to Cell Cycle Progression, Apoptosis 377
23.12 Chromosome 3q22.3 – Link to Adhesion Signaling 377
23.13 Chromosome 6p24 – Link to Coronary Calcification 377
23.14 Chromosome 6q26–27 – Link to Lp(a) 377
23.15 Chromosome 21q22 – No Functional Link Yet Established 378
23.16 Chromosome 12q24.3 – Link to LDL Metabolism 378
23.17 General Lessons from Modern CAD Genetics 378
23.18 Is Genetic Risk Prediction feasible? 379
23.19 Cardiovascular System Biology 380
23.20 Conclusion 381
References 381
24: Hereditary Neuromuscular Diseases and Cardiac Involvement 384
24.1 Introduction 384
24.2 Muscle Disorders 384
24.2.1 Muscular Dystrophies 384
24.2.1.1 Sarcolemma-Associated Proteins 384
Dystrophinopathic cardiomyopathy 384
Duchenne Muscular Dystrophy 385
Becker Muscular Dystrophy 386
X-Linked Dilated Cardiomyopathy 386
Female Carriers of Duchenne and Becker Muscular Dystrophy 386
Dystrophin-Associated Glycoprotein Complex Cardiomyopathies 386
Other Plasma Membrane Proteins 387
24.2.1.2 Proteins with Enzymatic Activity 387
LGMD2I/MDC1C 387
Fukuyama Congenital Muscular Dystrophy 387
24.2.1.3 Inner Nuclear Membrane Proteins 388
X-Linked Emery Dreifuss Muscular Dystrophy 388
Autosomal Dominant EDMD/LGMD1B 389
24.2.2 Nucleotide Repeat Disorders with Myotonia 389
24.2.2.1 Myotonic Dystrophy 389
24.2.2.2 Myotonic Dystrophy Type 2 390
24.2.3 Ion Channel Disorder Associated with Periodic Paralysis and Heart Involvement 390
24.2.3.1 Anderson Syndrome 390
24.2.4 Myofibrillar Myopathies 390
24.2.5 Congenital Myopathies 391
24.2.5.1 Central Core Disease 391
24.2.5.2 Nemaline Rod Myopathy 391
24.2.5.3 Myosin Storage Myopathy 391
24.2.6 Metabolic Disorders Affecting Muscle 391
24.2.6.1 Lysosomal Glycogenosis 391
Pompe’s Disease or Glycogen Storage Disease Type II 391
Danon Disease 392
24.2.6.2 Mitochondrial Disorders 392
Primary Disorders of Mitochondrial Function 392
Carnitine Deficiency 392
Friedreich’s ataxia 392
Barth Syndrome 393
24.3 Neuropathies 393
24.3.1 Familial Amyloid Polyneuropathy 393
24.3.2 Charcot-Marie-Tooth Disease Type 2 Caused by Lamin a/C Mutations 393
24.3.3 Refsum’s Disease 397
24.4 Summary 397
References 397
25: Sudden Cardiac Death in the Young Epidemiology and Cardiogenetic Evaluation of Victims and Their Relatives400
25.1 Introduction 400
25.2 Definitions 400
25.3 Incidence 402
25.4 Causes 403
25.5 Demographics 403
25.6 Postmortem Diagnosis 404
25.6.1 Circumstances of Death, Verification of the victim’s Medical History and Family History 404
25.6.2 Autopsy 404
25.6.2.1 DNA Storage 405
25.7 Cardiogenetic Evaluation of First-Degree Relatives of Young Sudden (Cardiac) Death Victims 405
25.7.1 Cardiogenetic Clinic 405
25.7.2 Genetic Testing 405
25.7.3 Evaluation of First-Degree Relatives 406
25.7.3.1 Cost-Effectiveness of Cardiogenetic Evaluation of First-Degree Relatives 407
25.8 Preparticipation Screening of Athletes 407
25.9 Key Messages 408
References 409
26: The Outpatient Clinic for Cardiogenetics 412
26.1 Introduction 412
26.2 Backgrounds of Genetic Counseling and Genetic Testing 413
26.2.1 Genetic Counseling 413
26.2.1.1 Components of Genetic Counseling Sessions for Cardiac Disease 413
26.2.1.2 Evidence-Based Protocols and Guidelines in Genetic Counseling for Cardiac Disorders 414
26.2.1.3 Reasons for Attending Genetic Counseling for Cardiac Disease 414
26.2.2 Genetic Testing 415
26.2.2.1 Diagnostic Testing 415
26.2.2.2 Predictive Testing 415
26.2.2.3 Genetic (Population) Screening 416
26.2.2.4 Cascade Screening 416
26.3 State of the Art in Cardiogenetic Counseling and Testing in the Netherlands 416
26.3.1 Background of Genetic Counseling and Testing in Inherited Cardiovascular Disease 416
26.3.1.1 From a Clinical Genetic Point of View 416
26.3.1.2 From a Public Health Point of View 417
26.4 Current Genetic Counseling and Testing for Genetic Cardiovascular Diseases in the Netherlands 417
26.4.1 Multidisciplinary Outpatient Clinics for Cardiogenetics 417
26.4.2 Current Cascade Screening in Familial Hypercholesterolemia 419
26.4.3 Diagnostic Testing and Counseling in Diseases Associated with Aortic Dissections 419
26.4.4 Diagnostic Testing and Counseling in Congenital Heart Defects 420
26.4.5 Expected Future Developments 420
26.4.6 Summary 420
References 421
27: Abdominal Aortic Aneurysm 422
27.1 Introduction 422
27.2 Epidemiology 422
27.3 Pathogenesis 423
27.3.1 Natural History 423
27.3.2 Vascular Pathology 423
27.4 Molecular Genetics 424
27.4.1 Segregation and Linkage Analysis 424
27.4.2 Association Studies 425
27.5 Clinical Diagnosis 426
27.5.1 Diagnosis of Unruptured AAA 427
27.5.1.1 Future Genetic Diagnostic Tools 428
27.5.2 Diagnosis of Ruptured AAA 428
27.6 Follow-up/Therapy 428
27.6.1 Follow-up 428
27.6.2 Therapy 429
27.6.2.1 Lifestyle 429
27.6.2.2 Pharmacological Treatment 429
27.6.2.3 Surgical Intervention 429
27.7 Summary 430
References 430
28: Future of Cardiogenetics 435
28.1 Phase 1: Translation of Basic Cardiogenomics Research into a Candidate Health Care Application 435
28.1.1 Diagnostic Testing 435
28.1.2 Genetic Screening 436
28.1.3 Prediction of Risk 437
28.1.4 Pharmacogenetics 437
28.2 Phase 2: Research Assesses the Value of a Genomic Application for Health Practice Leading to the Development of Evidence-B 437
28.3 Phase 3: Research Attempts to Move Evidence-Based Guidelines into Health Practice, Through Delivery, Dissemination, and Di 438
28.4 Phase 4: Evaluation of Impact of Evidence-Based Recommendations and Guidelines on Real-World Health Outcomes 438
References 439
Appendix 441
Index 444