Clinical Molecular Medicine: Principles and Practice

Cover......Page 1
Clinical Molecular Medicine: Principles and Practice
......Page 3
Copyright......Page 4
Dedication......Page 5
Dedication......Page 6
Contents......Page 7
List of contributors......Page 12
About the author......Page 15
Foreword......Page 16
Preface......Page 17
Acknowledgement and Disclaimer......Page 19
Section 1: Fundamentals of molecular medicine
......Page 21
1.2 Hereditary factors: genes, genetics, and genomics......Page 22
1.2.1 Structure and organization of nucleic acids......Page 23
1.3 Human genome variation and human disease......Page 26
1.3.1 Measuring genetic and genomic variation......Page 27
1.3.2 Genome variation and human disease......Page 28
1.4 The mitochondrial genome......Page 29
1.5 Functional genomics, transcriptomics, and proteomics......Page 31
1.7 Human genomics for socioeconomic development......Page 33
References......Page 34
2.1 Plasma membrane......Page 36
2.1.1 Cell signaling......Page 37
2.1.2 Cell junctions......Page 38
2.2 Cytoskeleton......Page 40
2.3.1 Chromosome territories, gene transcription and the nuclear lamina......Page 42
2.3.2 Cajal bodies, speckles and pre-mRNA processing......Page 48
2.3.4 Nuclear envelope and mRNA quality control......Page 49
2.4.1 Ribosomes and mRNA translation......Page 51
2.5 Vesicular trafficking: the secretory and endocytic pathways......Page 53
2.6 Protein turnover and cell size control......Page 57
2.7.1 The cell cycle......Page 58
2.7.2 Primary cilium......Page 60
2.8.1 Mitochondria......Page 61
2.9 Summary......Page 63
Bibliography......Page 64
3.2.1 Inborn errors of metabolism......Page 65
3.2.2 Metabolomics in cancer and other human diseases......Page 67
3.2.3 Other applications of clinical metabolomics......Page 68
3.3 Techniques used in metabolomics and databases......Page 69
References......Page 70
4.1 Introduction......Page 74
4.2.2 Second- (next-) generation sequencing......Page 75
4.3 Choice of test......Page 76
4.3.1 Small gene panels......Page 77
4.3.2 Whole-exome sequencing and large curated panels......Page 78
4.6 Ethical considerations......Page 79
4.7 Bioinformatics......Page 82
4.8.2 Computational and predictive data......Page 83
4.8.4 De novo status and segregation data......Page 84
4.8.9 Summary: potential future developments in clinical genomics......Page 85
Section II: Molecular medicine in clinical practice
......Page 87
5.1.2 Obesity: nature or nurture......Page 88
5.2.1.3 Family history......Page 89
5.2.3 Case 3......Page 90
5.3.2 Case 2. Leptin receptor deficiency......Page 92
5.3.3 Case 3. 16p11.2 deletion......Page 93
5.4.4 The energy balance......Page 94
5.4.8.1 Prader–Willi syndrome......Page 96
5.4.8.2 Bardet–Biedl syndrome......Page 97
5.5.4.1 Lifestyle interventions......Page 98
5.5.4.2 Bariatric surgery......Page 99
5.5.5.2 Personalized treatment......Page 100
References......Page 101
Guide to further reading: articles......Page 102
Online material......Page 103
6.1.1 Limitations of “clinical” dysmorphology and the newer dysmorphology tools......Page 104
6.1.2 Molecular dysmorphology......Page 105
6.2 Clinical cases and molecular basis......Page 106
Holoprosencephaly......Page 107
Split hand–foot malformation......Page 108
Laminopathies......Page 109
Ciliopathies......Page 110
6.2.2 Epigenetic mechanisms and transcriptomopathies......Page 111
6.2.3 Spliceopathies......Page 112
6.3 Molecular diagnosis and therapy......Page 113
Duchenne muscular dystrophy......Page 114
Achondroplasia......Page 115
Autosomal dominant polycystic kidney disease......Page 116
Farber/Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)......Page 117
6.4 Conclusion/summary......Page 118
References......Page 119
7.1 Introduction......Page 121
7.2 Sex chromosome disorder of sex development......Page 122
7.3.1 Disorders of testicular (gonadal) development......Page 124
7.3.2.1 Disorders of androgen synthesis associated with adrenal dysfunction......Page 125
7.3.3 Disorders of androgen response......Page 126
7.4.1 Ovarian development......Page 127
7.4.2.2 Steroid synthesis defects—overproduction of androgens......Page 128
7.5 Investigations......Page 129
7.6 Gender assignment......Page 130
References......Page 131
8.3 Normal development of the heart......Page 134
8.4.1 Genome-wide association studies......Page 135
8.5.1 Congenital heart disease and copy-number variations......Page 136
8.6 Single-gene (Mendelian) disorders......Page 137
8.6.2.1 CHARGE association......Page 138
8.7 The noncoding regulatory genome in congenital heart disease: microRNAs and circular RNAs......Page 139
8.7.1 Congenital heart disease and single-nucleotide polymorphisms......Page 140
8.9.1 DNA methylation......Page 141
References......Page 142
9.2.2 Case 2......Page 145
9.2.3 Case 3......Page 146
9.3.3 The sarcoplasmic reticulum and excitation–contraction coupling......Page 147
9.4.1 Mechanisms of channelopathy......Page 149
9.4.2.2 Long QT syndrome diagnosis......Page 150
9.4.2.2.1 Long QT syndrome type 1......Page 151
9.4.2.2.2 Long QT syndrome type 2......Page 152
9.4.3 Molecular risk stratification in long QT syndrome......Page 153
9.4.5 Generation and propagation of arrhythmia in long QT syndrome......Page 155
9.5.1 Generation and propagation of arrhythmia......Page 156
9.6.2 Molecular risk stratification in catecholaminergic polymorphic ventricular tachycardia......Page 157
9.7.1 Generation and propagation of arrhythmia in Brugada syndrome......Page 158
9.8.1.2 Targeted therapies in long QT syndrome......Page 159
9.8.3.1 Clinical risk assessment and therapy in catecholaminergic polymorphic ventricular tachycardia......Page 160
9.8.4.2 Targeted therapy in Brugada syndrome......Page 161
References......Page 162
10.2 Epidemiology......Page 165
10.3 Etiology of heart failure......Page 166
10.4.4.2 Cardiomyopathy screen......Page 167
10.4.5.2 Ambulatory electrocardiography......Page 168
10.4.6.1 Plain chest radiography......Page 169
10.4.6.2 Echocardiography......Page 170
10.4.6.3 Cardiac magnetic resonance imaging......Page 171
10.4.8 Cardiac biopsy......Page 172
10.5.3 The genetic basis of the inheritable cardiomyopathies......Page 173
10.5.4.1 Diagnostic confirmation and prognostication in clinically suspected cases......Page 174
10.5.7 Limitations of genetic testing in heart failure......Page 175
10.6.1 Pharmacological therapies......Page 176
10.6.3 Exercise......Page 177
References......Page 178
11.2.1 Endothelium......Page 181
11.3 Genetics of hypertension......Page 182
11.4.1.2 Definition......Page 183
11.4.1.3 Genetics......Page 184
11.4.1.4.1 WNK kinases......Page 185
11.4.1.4.2 KLHL3 and CUL3 proteins......Page 186
11.4.2.2 Definition......Page 187
11.4.2.4 Pathophysiology......Page 188
11.4.2.5 Diagnosis......Page 189
CYP11B1 gene......Page 190
11.4.3.4 Definition of 17 α-hydroxylase deficiency......Page 191
11.4.3.6 Pathophysiology of 17 α-hydroxylase deficiency......Page 192
11.5.2 Definition......Page 193
11.5.6 Management......Page 194
11.6 Genetic overlap of monogenic and essential hypertension......Page 195
11.8 Future perspectives......Page 196
References......Page 197
12.3 Single-gene disorders associated with stroke......Page 200
12.4 Genetics of common forms of stroke......Page 202
12.4.2 Molecular pathophysiology of ischemic stroke......Page 203
12.4.3 Molecular genetics of ischemic stroke......Page 205
12.4.3.1 Phosphodiesterase 4D, cAMP-specific gene......Page 207
12.4.3.2 Arachidonate 5-lipoxygenase-activating protein gene......Page 208
12.4.3.4 Ninjurin 2 gene......Page 209
12.4.4 Molecular pathophysiology of intracerebral hemorrhage......Page 210
12.4.5.1 Apolipoprotein E gene......Page 212
12.4.6 Molecular pathophysiology of intracranial aneurysm and subarachnoid hemorrhage......Page 213
12.4.7.2 Tumor necrosis factor receptor superfamily, member 13B gene......Page 216
12.6 Conclusion......Page 218
References......Page 219
Further reading......Page 227
13.2.1.1.1 Clinical case......Page 228
Management of congenital hypopituitarism......Page 229
13.2.2.2 Clinical case......Page 230
Overview of the relevant molecular systems underpinning the clinical scenario......Page 231
13.2.3 Genetics of pituitary adenoma......Page 232
13.3.1.1.1 Clinical case......Page 233
13.3.1.1.2 Discussion with reflection on the molecular systems underpinning the clinical scenario......Page 234
13.3.1.2.2 Medical management......Page 236
13.4.1.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario......Page 238
13.4.2.2 Clinical case......Page 239
13.4.2.2.3 Management of patients with X-linked hypophosphatemia......Page 240
13.5.2 Clinical case......Page 241
13.5.2.2 Overview of the relevant molecular systems underpinning the clinical scenario......Page 242
13.5.3 Management of patients with primary hyperaldosteronism......Page 243
13.6.2 Clinical case......Page 244
13.6.2.2 Management......Page 245
13.6.3.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario......Page 246
13.7.2 Clinical case......Page 247
13.7.2.2 Overview of the relevant molecular systems underpinning the clinical scenario......Page 248
13.8.1.2 Clinical case......Page 251
Introduction......Page 252
References......Page 253
14.2 An outline of lipoprotein metabolism......Page 256
14.3 The environmental and genetic factors affecting lipid metabolism......Page 258
14.6 Common (polygenic) hypercholesterolemia......Page 260
14.8 Characteristic clinical features of familial hypercholesterolemia......Page 263
14.10 Genetic disorders resulting in hypertriglyceridemia......Page 266
14.13 Management of hypercholesterolemia......Page 267
References......Page 271
Further reading......Page 276
15.2 Molecular basis of glycemic homeostasis......Page 277
15.2.3 Role of insulin and insulin receptor......Page 278
15.3.1 Molecular mechanisms in type 1 diabetes mellitus......Page 280
15.3.4 Autoimmunity and type 1 diabetes mellitus......Page 282
15.3.6.2 Genetic factors in T2DM......Page 283
15.4.1 Clinical manifestations......Page 284
15.4.2 Blood glucose parameters—World Health Organization criteria......Page 285
15.5.1 Neurobiological factors......Page 286
15.5.2 Nutritional factors—high glycemic foods......Page 287
15.5.3 Constitutional and medical obesity......Page 288
15.5.4.2 Rare monogenic diseases and syndromes of obesity......Page 289
15.5.4.4 Environment and epigenetics/epigenomics......Page 290
15.6 Vitamin D and diabetes mellitus......Page 291
15.7.2 Maturity onset diabetes of the young (OMIM 125850)......Page 293
15.7.5 Malformation syndromes with diabetes mellitus......Page 294
15.8.3 Oral antidiabetic drugs......Page 295
15.9 Summary......Page 296
References......Page 297
Further reading......Page 298
16.2 What are seizures?......Page 299
16.3 What is epilepsy?......Page 300
16.4 Evidence for the genetic basis of epilepsies......Page 301
16.5 The genetic architecture of epilepsies......Page 302
16.5.2 Genome-wide association studies......Page 303
16.5.4 Rare coding sequence variants in common epilepsies......Page 304
16.5.5 Noncoding variants......Page 305
16.5.7 Copy number variation......Page 306
16.6.3 Recognized mitochondrial epilepsy syndromes......Page 308
16.8.1 Human leukocyte antigens and adverse antiepileptic drug reactions......Page 309
16.9 Molecular genetic testing strategies for epilepsy......Page 310
16.9.1 Genetic testing methods......Page 311
16.9.2 Limitations to current genetic testing strategies......Page 312
References......Page 314
17.1 Introduction......Page 319
17.2 Human leukocyte antigen system......Page 320
17.3 Human leukocyte antigen and disease......Page 322
17.3.1 Human leukocyte antigen and drug-induced hypersensitivities......Page 323
17.4.1 Human leukocyte antigen-C expression and disease development......Page 324
17.4.4 Low versus high expression mismatches in transplantation......Page 325
17.4.6 Mechanisms underlying allele-specific human leukocyte antigen expression......Page 326
17.5.1 Allorecognition......Page 327
17.5.4 Complement activation......Page 328
17.6 Human leukocyte antigen–antibody-detection techniques......Page 329
17.6.2 Role of non–human leukocyte antigen antibodies......Page 330
17.6.3 Preventive measures......Page 331
17.7 Human leukocyte antigen and blood transfusion......Page 332
References......Page 333
Further reading......Page 335
18.2.2 Characteristics of the α-globin and β-globin gene loci......Page 336
18.3.1 β Thalassemia......Page 337
18.3.4 Mutants that affect β-globin mRNA translation......Page 338
18.5.3 Trans acting mutations associated with β thalassemia......Page 339
18.7.3 Preimplantation genetic diagnosis......Page 340
18.8.3 Laboratory diagnosis of α-deletions, point mutations and triplications......Page 341
18.8.4 Thalassemia intermedia: Molecular genetics and genotype–phenotype correlation......Page 342
18.9.1 Sickle-cell hemoglobin......Page 343
18.9.4 Hemoglobin M or methemoglobinemic hemoglobin variants......Page 344
18.9.8 Defects of erythroid heme biosynthesis......Page 345
References......Page 346
Further reading......Page 348
19.1 Introduction......Page 349
19.2.3.1 Antithrombin deficiency......Page 351
19.2.3.3 Factor V Leiden......Page 352
19.3.2 Hemophilia A (factor VIII deficiency)......Page 353
19.3.3.1 von Willebrand disease......Page 354
19.4.2 Ehlers–Danlos syndrome......Page 356
19.6 Conclusion......Page 357
References......Page 358
20.2 Genomics of bronchial asthma......Page 361
20.3.1 Segregation analysis......Page 362
20.3.2 Twin genetic studies......Page 363
20.3.3 Genetic linkage......Page 364
20.3.4 Candidate gene studies......Page 365
20.3.5 Genome-wide association studies......Page 367
20.3.6 Next-generation sequencing......Page 370
20.5 Conclusion......Page 371
References......Page 372
21.2 Complex clinical predisposition with complex complications......Page 375
21.2.2 Genome versus environome......Page 377
21.2.3 Genetics and genomics......Page 378
21.2.5 Transcriptome......Page 381
21.3 The identification of the NOD2 gene......Page 382
21.4 NOD2 and innate immunity......Page 383
21.4.3 The Ancestor’s tale of mutations that predispose to inflammatory bowel disease......Page 384
21.5 Major histocompatibility complex (6p21)......Page 385
21.6 The causative genome variants and functional implications......Page 386
21.9 Mucosal barrier function......Page 387
21.11 Clinical implications and translation......Page 388
References......Page 389
Further reading......Page 396
22.1 Introduction......Page 397
22.2 Molecular pathology of acute inflammation (sepsis and trauma)......Page 398
22.3 Molecular pathology of chronic inflammation......Page 399
22.4 Age-associated chronic inflammation......Page 400
22.5.1 Genomic and molecular diagnosis......Page 402
22.5.2.1.1 Genetic factors......Page 403
22.5.2.1.2 Molecular pathology......Page 404
22.5.2.1.4 Articular features......Page 405
22.5.2.1.6 Treatment......Page 406
22.5.2.2 Systemic lupus erythematosus......Page 407
22.6 Summary......Page 408
References......Page 409
23.1 Introduction......Page 411
23.2.3 Chemokine receptor genetic variants affecting HIV-1 mother-to-child transmission in absence of antiretrovirals......Page 412
23.3 Clinical relevance of human leukocyte antigen gene variants in HBV infection......Page 413
23.4.5 Human leukocyte antigen gene variants and efficacy of interferon alfa and NAs treatment......Page 414
23.5.3 Genes involved in T-cell regulation and function......Page 415
23.6 Host genetic susceptibility to human papillomavirus infection and development of cervical cancer......Page 416
23.7 Host genetics of Epstein–Barr infection......Page 417
23.8.2 Cytokine polymorphism and dengue......Page 418
23.9.3 Genetic susceptibility to severe influenza......Page 419
23.10.1 Mycobacterium tuberculosis......Page 420
23.10.3 Chlamydia trachomatis......Page 421
23.10.6 Coxiella burnetii......Page 422
23.11.1 Candida......Page 423
23.11.3 Cryptococcus neoformans and Cryptococcus gattii......Page 424
23.12.1.1 Hemoglobin alterations—hemoglobinopathies......Page 425
23.12.2 Immune response......Page 426
23.13.3 Innate immune response and cellular injury......Page 427
References......Page 428
24.2 Inherited and familial cancer......Page 430
24.4.1 The breast and ovarian cancer......Page 431
24.5.2 RAS–MAPK syndromes......Page 432
24.6 Genetic imprinting and cancer......Page 433
24.8 Inherited susceptibility to leukemia......Page 434
24.10 Genetic counseling for inherited cancer susceptibility......Page 437
24.11 Diagnostic and predictive genetic testing for cancer......Page 438
References......Page 441
Further reading......Page 443
25.2 Acute kidney injury......Page 444
25.3 Chronic kidney disease......Page 445
25.3.3 Understanding pathogenesis of chronic kidney disease......Page 446
25.4.1 Targeted gene panel analysis in chronic kidney disease......Page 447
25.4.5 Genetic counseling......Page 448
25.6 Conclusion......Page 449
References......Page 450
26.1 Introduction......Page 453
26.2 Neurodegenerative disease clinical case studies and molecular systems underpinning the clinical scenario......Page 454
26.2.1 Alzheimer’s disease......Page 455
26.2.2 Parkinson’s disease......Page 457
26.2.3 Frontotemporal dementia......Page 458
26.3 Molecular pathology of neurodegenerative diseases......Page 459
26.4 Application of molecular diagnostics in neurodegeneration......Page 462
26.5 Summary......Page 464
References......Page 465
27.2.2.1.1 SNCA/PARK1: alpha-synuclein gene......Page 467
27.2.2.1.2 LRRK2/PARK8: leucine-rich repeat kinase 2......Page 468
27.2.3.4 Glucocerebrosidase mutations......Page 469
27.3.1 Clinical characteristics......Page 470
27.3.5 Diagnosis of dystonia......Page 471
27.3.5.3 DYT6: THAP1 mutations......Page 475
27.3.6 Therapy of dystonia......Page 476
27.3.7 Dystonia: key learning points......Page 477
27.4 Ataxia......Page 478
27.4.1.5 Mitochondrial dysfunction......Page 481
27.4.5 Spinocerebellar ataxia 2......Page 482
27.4.7 Spinocerebellar ataxia type 7......Page 484
27.4.9 Potential future targets for molecular therapy......Page 485
27.6.2 Wilson’s disease......Page 486
27.6.3.2 Phospholipase A2-associated neurodegeneration......Page 487
27.6.3.8 Aceruloplasminaemia......Page 488
References......Page 489
28.2 Copy number variation in psychiatric disorders......Page 492
28.4 Penetrance of copy number variations......Page 494
28.5 Results from genome-wide association studies......Page 495
28.6 High-throughput sequencing studies......Page 497
28.8 Conclusions......Page 498
References......Page 499
29.2 Oncogene addiction......Page 501
29.4 Histology agnostic treatment......Page 503
29.5 Limitations of molecularly targeted therapy in cancer......Page 504
29.7 Conclusion......Page 505
References......Page 506
30.2.1 Recombinant pharmacotherapy......Page 508
30.2.2 Recombinant vaccines......Page 509
30.2.2.3 HIV vaccines......Page 510
30.3 Stem-cell therapy......Page 511
30.4 Gene therapy......Page 513
30.5 Antisense oligonucleotides......Page 515
30.6 Ribozymes......Page 516
30.7 RNA interference......Page 517
30.8 Aptamers......Page 518
30.9 Gene and genome editing......Page 519
Disclaimer and acknowledgments......Page 522
References......Page 523
31.1 Introduction and historical perspective......Page 524
31.2 The Human Genome Project......Page 525
31.4 Genetic and molecular basis of the individual drug-response variation......Page 526
31.4.2 Genetic factors in pharmacodynamics......Page 527
31.5.2 Warfarin use as an anticoagulant—tailoring an individual’s dose using preprescription genetic information—testing fo.........Page 529
31.5.3.2 HLA testing for prediction Stevens–Johnson syndrome with the use of the antiepileptic carbamazepine......Page 530
31.7.2 Limitations of single-nucleotide polymorphism testing in isolation......Page 531
31.7.3 Physician barriers......Page 532
31.8 Clinical pharmacogenetics implementation consortium—helping clinicians understand and apply pharmacogenetic informatio.........Page 533
31.9 Pharmacogenomics and drug development—novel study designs in precision medicine......Page 534
31.11 Resources to collect and curate pharmacogenetic variants......Page 535
References......Page 536
Further reading......Page 537
32.2 Genetic, genomic, and molecular revolutions in medicine......Page 538
32.3 Evidence-based, precision, and personalized medicine......Page 540
32.4 The stratified medicine......Page 542
32.6 Summary......Page 544
References......Page 546
Glossary—molecular medicine*......Page 547
Index......Page 556
Back Cover......Page 581