Clinical Molecular Medicine : Principles and Practice

Clinical Molecular Medicine: Principles and Practice presents the latest scientific advances in molecular and cellular biology, including the development of new and effective drug and biological therapies and diagnostic methods. The book provides medical and biomedical students and researchers with a clear and clinically relevant understanding on the molecular basis of human disease. With an increased focus on new practice concepts, such as stratified, personalized and precision medicine, this book is a valuable and much-needed resource that unites the core principles of molecular biology with the latest and most promising genomic advances. Key Features Illustrates the fundamental principles and therapeutic applications of molecular and cellular biology Offers a clinically focused account of molecular heterogeneity Includes comprehensive coverage of many different disorders, including growth and development, cardiovascular, metabolic, skin, blood, digestive, inflammatory, neuropsychiatric disorders, and many more Readership Medical and biomedical students, clinicians and scientists who are expected to have a clear and clinically relevant understanding of the molecular basis of human disease to practice evidence-based clinical medicine 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