Clinical Molecular Medicine: Principles and Practice PDF
Preview Clinical Molecular Medicine: Principles and Practice
CLINICAL MOLECULAR MEDICINE CLINICAL MOLECULAR MEDICINE Principles and Practice Edited by D K HAVENDRA UMAR TheWilliamHarveyResearchInstitute,BartsandTheLondonSchoolofMedicine&Dentistry, QueenMaryUniversityofLondon,London,UnitedKingdom Academic Press isan imprint of Elsevier 125 London Wall, London EC2Y 5AS, UnitedKingdom 525 BStreet, Suite 1650, San Diego, CA 92101,United States 50 Hampshire Street, 5th Floor, Cambridge,MA 02139,United States TheBoulevard, LangfordLane,Kidlington, OxfordOX5 1GB,United Kingdom Copyright© 2020 Elsevier Inc. All rights reserved. Nopartof this publication maybereproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording,or any information storage and retrieval system, without permission in writingfrom the publisher.Details onhow to seek permission,further informationabout the Publisher’s permissions policies and our arrangements with organizations such as the Copyright ClearanceCenter and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions containedin it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledgeand best practice in this field areconstantly changing.As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may becomenecessary. Practitioners and researchers must always rely on their own experience andknowledge in evaluatingand using any information, methods, compounds, or experiments described herein. Inusingsuch information or methods they shouldbe mindful of theirown safety andthe safety of others,including parties forwhom theyhave a professionalresponsibility. To the fullest extent of the law, neither the Publishernor the authors, contributors, or editors,assume any liabilityforany injury and/or damageto personsor propertyas amatter of products liability, negligenceor otherwise, or from any use or operation of any methods, products, instructions, or ideas containedin the materialherein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library ofCongress Cataloging-in-Publication Data A catalog record for this book isavailable from the Library of Congress ISBN: 978-0-12-809356-6 For Information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Andre Gerhard Wolff Acquisition Editor: Erin Hill-Parks EditorialProjectManager: Megan Ashdown ProductionProjectManager: Stalin Viswanathan Cover Designer:Miles Hitchen Typeset by MPS Limited,Chennai, India Dedication Dedicated to The Late Sir David Weatherall (1933(cid:1)2019) GBE, FRS, DM, FRCP Emeritus RegiusProfessorof Medicine, University of Oxford, Oxford, United Kingdom Founder/Director—Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom Dedication To my Parents showering blessingsfrom theheaven Wife, Anju, for life-long support, confidence, and sharing my passionfor books Children,Ashish and Jaime, Nikita and Mayank for their goodwill and trusting me Grand children,Jaya, Arya, Anya, and Krish, for theirjoyful presence anda reminderof the future Contents List of contributors xv 3.3 Techniquesusedinmetabolomicsand databases 51 About the author xix 3.4 Conclusions 52 Foreword xxi Acknowledgments 52 Preface xxiii References 52 Acknowledgement and Disclaimer xv 4. Clinical applications of next-generation I sequencing 57 FUNDAMENTALS OF MOLECULAR IANTULLY MEDICINE 4.1 Introduction 57 4.2 Next-generationsequencingtechnologies 58 4.3 Choiceoftest 59 1. The human genome and molecular medicine 3 4.4 Whole-genomesequencing 62 4.5 Summary 62 DHAVENDRAKUMAR 4.6 Ethicalconsiderations 62 1.1 Introduction 3 4.7 Bioinformatics 65 1.2 Hereditaryfactors:genes,genetics,andgenomics 3 4.8 Clinicalinterpretationofvariants 66 1.3 Humangenomevariationandhumandisease 7 1.4 Themitochondrialgenome 10 II 1.5 Functionalgenomics,transcriptomics,andproteomics 12 1.6 Translationalhumangenomics 14 MOLECULAR MEDICINE IN 1.7 Humangenomicsforsocioeconomicdevelopment 14 1.8 Conclusions 15 CLINICAL PRACTICE References 15 5. Molecular basis of obesity disorders 73 2. Cellular structure and molecular cell biology 17 LOTTEKLEINENDORSTANDMIEKEM.VANHAELST LUCIANAAMARALHADDAD 5.1 Introduction 73 2.1 Plasmamembrane 17 5.2 Clinicalcases 74 2.2 Cytoskeleton 21 5.3 Molecularsystemsunderpinningtheclinical 2.3 Cellnucleusandgeneexpression 23 scenario 77 2.4 Proteinsynthesis 32 5.4 Molecularbiologyandpathophysiologyofobesity 79 2.5 Vesiculartrafficking:thesecretoryandendocytic 5.5 Targetedmoleculardiagnosisandtherapy 83 pathways 34 5.6 Summary 86 2.6 Proteinturnoverandcellsizecontrol 38 References 86 2.7 Microtubule-organizingcentersandthecellcycle 39 Guidetofurtherreading:articles 87 2.8 Energyproductionandoxidativestress 42 2.9 Summary 44 Bibliography 45 6. Molecular dysmorphology 89 KOUMUDIGODBOLE 3. Molecular basis of clinical metabolomics 47 6.1 Introduction 89 DIEGOF.GOMEZ-CASATIANDMARI´AV.BUSI 6.2 Clinicalcasesandmolecularbasis 91 6.3 Moleculardiagnosisandtherapy 98 3.1 Introduction 47 6.4 Conclusion/summary 103 3.2 Clinicalapplicationsofmetabolomics 47 References 104 ix x CONTENTS 7. Disorders of sex development 107 11. Molecular pathophysiology of systemic hypertension 169 PIERRESINAJON,SALEHALBANYANANDDAVIDCHITAYAT TATIANAGAROFALIDOUANDPATRICIAB.MUNROE 7.1 Introduction 107 7.2 Sexchromosomedisorderofsexdevelopment 108 11.1 Introduction 169 7.3 46,XYdisordersofsexualdifferentiation 110 11.2 Bloodpressureregulation—keysystems 169 7.4 46,XXdisordersofsexdevelopment 113 11.3 Geneticsofhypertension 170 7.5 Investigations 115 11.4 Monogenicformsofsystemichypertension 171 7.6 Genderassignment 116 11.5 Familialhyperaldosteronism;type1—glucocorticoid 7.7 Gonadalcancerrisk 117 remediablealdosteronism 181 7.8 Conclusion 117 11.6 Geneticoverlapofmonogenicandessential 7.9 ResourcesWeb-basedresources 117 hypertension 183 References 117 11.7 Clinicalimplicationsfromgeneticstudiesof hypertension 184 11.8 Futureperspectives 184 8. Molecular systems in cardiovascular Acknowledgments 185 developmental disorders 121 References 185 ALANGRAHAMSTUART 8.1 Introduction 121 12. Molecular basis of stroke 189 8.2 Historicaloverview 121 YOSHIJIYAMADA 8.3 Normaldevelopmentoftheheart 121 8.4 Advancesintechnology 122 12.1 Introduction 189 8.5 Chromosomalaneuploidyandstructuralheartdisease 123 12.2 Geneticsofstroke 189 8.6 Single-gene(Mendelian)disorders 124 12.3 Single-genedisordersassociatedwithstroke 189 8.7 Thenoncodingregulatorygenomeincongenital 12.4 Geneticsofcommonformsofstroke 191 heartdisease:microRNAsandcircularRNAs 126 12.5 Clinicalimplication 207 8.8 Noncardiaccongenitalanomaliesincongenitalheart 12.6 Conclusion 207 disease 128 References 208 8.9 Theepigenomeandcongenitalheartdisease 128 Furtherreading 216 8.10 Futureconsiderations 129 References 129 13. Clinical molecular endocrinology 217 ATULKALHAN 9. Channelopathies in clinical medicine—cardiac arrhythmias 133 13.1 Introduction 217 13.2 Congenitalhypopituitarism,congenital JULIANO.M.ORMERODANDELIJAHR.BEHR hypogonadotropichypogonadism,andpituitary 9.1 Introduction 133 adenoma 217 9.2 Clinicalcases 133 13.3 Primaryhyperparathyroidismandmultipleendocrine 9.3 Molecularsystemsunderpinningtheclinicalscenario 135 neoplasiasyndromes 222 9.4 Overviewofmolecularbiologyandpathophysiology 137 13.4 Chronichypocalcemiaandhypophosphatemia 227 9.5 ShortQTsyndrome 144 13.5 Primaryhyperaldosteronism 230 9.6 Catecholaminergicpolymorphicventriculartachycardia 145 13.6 Congenitaladrenalhyperplasia,apparent 9.7 Brugadasyndrome 146 mineralocorticoidexcess,andrenaltubulardefects 233 9.8 Targetedmoleculardiagnosisandtherapy 147 13.7 Pheochromocytomaandparaganglioma 236 9.9 Summary 150 13.8 Primarygonadalfailureandandrogen References 150 resistance/insensitivitysyndrome 240 References 242 10. Chronic heart failure 153 14. Genetic disorders of lipoprotein metabolism 245 ABBASZAIDIANDPARINSHAH DEEPAKBHATNAGAR,JONATHANSCHOFIELDAND 10.1 Introduction 153 HANDREANSORAN 10.2 Epidemiology 153 10.3 Etiologyofheartfailure 154 14.1 Introduction 245 10.4 Clinicalassessment 155 14.2 Anoutlineoflipoproteinmetabolism 245 10.5 Genetictesting 161 14.3 Theenvironmentalandgeneticfactorsaffectinglipid 10.6 Management 164 metabolism 247 References 166 14.4 Screeningforlipoproteindisorders 249 CONTENTS xi 14.5 Diagnosinggeneticdisordersoflipoprotein 17.6 Humanleukocyteantigen(cid:1)antibody-detection metabolism 249 techniques 319 14.6 Common(polygenic)hypercholesterolemia 249 17.7 Humanleukocyteantigenandbloodtransfusion 322 14.7 Familialhypercholesterolemia 252 17.8 Conclusions 323 14.8 Characteristicclinicalfeaturesoffamilial References 323 hypercholesterolemia 252 Furtherreading 325 14.9 Screeningstrategiesforfamilialhypercholesterolemia 255 14.10 Geneticdisordersresultinginhypertriglyceridemia 255 18. Disorders of abnormal hemoglobin 327 14.11 Type3hyperlipoproteinemia 256 14.12 Treatmentofprimarylipoproteindisorders 256 REENADASANDPRASHANTSHARMA 14.13 Managementofhypercholesterolemia 256 18.1 Introduction 327 14.14 Agentsindevelopment 260 18.2 Thehemoglobinmolecule:normalstructureand 14.15 Managementofhypertriglyceridemia 260 function 327 References 260 18.3 Theclassificationandgeneticsofthethalassemias 328 Furtherreading 265 18.4 Genedeletionsinβthalassemia 330 18.5 Otherlesscommon,specificmolecularcauses 15. Molecular medicine of diabetes mellitus 267 ofβthalassemia 330 18.6 Laboratorydiagnosisofβthalassemia 331 DHAVENDRAKUMAR 18.7 Preventionofβthalassemia 331 18.8 αThalassemia 332 15.1 Introduction 267 18.9 Qualitativedefects(structuralhemoglobinvariants 15.2 Molecularbasisofglycemichomeostasis 267 andotherabnormalities) 334 15.3 Disordersoftheglycemicregulation 270 18.10 Summary 337 15.4 Diagnosisofdiabetesmellitus 274 References 337 15.5 Overweight,obesity,anddiabetesmellitus 276 Furtherreading 339 15.6 VitaminDanddiabetesmellitus 281 15.7 Inheritedmonogenicdiabetesmellitus 283 15.8 Managementofdiabetesmellitus 285 19. Coagulation and bleeding disorders 341 15.9 Summary 286 INDUSINGHANDRAGHUINDERSINGH References 287 Furtherreading 288 19.1 Introduction 341 19.2 Geneticbasisofthrombosis 343 19.3 Geneticbasisofthebleedingdisorders 345 16. Molecular genetic management of epilepsy 289 19.4 Structuraldefectsofthevascularsystem 348 DAVIDLEWIS-SMITH,DONALDP.CRAIG,NAOMIJ.P.THOMAS, 19.5 Inheriteddefectsofplatelets 349 KHALIDHAMANDIANDRHYSH.THOMAS 19.6 Conclusion 349 Conflictofinterest 350 16.1 Introduction 289 Author’sroles 350 16.2 Whatareseizures? 289 References 350 16.3 Whatisepilepsy? 290 16.4 Evidenceforthegeneticbasisofepilepsies 291 16.5 Thegeneticarchitectureofepilepsies 292 20. Molecular and genomic basis of bronchial 16.6 Mitochondrialepilepsies 298 asthma 353 16.7 Progressivemyoclonicepilepsies 299 ANUBHUTIGUPTA,SAMARPANACHAKRABORTYAND 16.8 Pharmacogeneticsofepilepsy 299 ANURAGAGRAWAL 16.9 Moleculargenetictestingstrategiesforepilepsy 300 16.10 Summary 304 20.1 Introduction 353 References 304 20.2 Genomicsofbronchialasthma 353 20.3 Geneticandgenomicstudiesinbronchialasthma 354 20.4 Managementandtreatmentofbronchialasthma 363 17. The human leukocyte antigen system in 20.5 Conclusion 363 human disease and transplantation medicine 309 References 364 GAURAVSHARMA,AJAYKUMARBARANWALAND NARINDERKUMARMEHRA 21. Molecular systems in inflammatory bowel 17.1 Introduction 309 disease 367 17.2 Humanleukocyteantigensystem 310 SAADPATHAN 17.3 Humanleukocyteantigenanddisease 312 17.4 Humanleukocyteantigenexpression:anexplanation 21.1 Introduction 367 fordiseasedevelopment 314 21.2 Complexclinicalpredispositionwithcomplex 17.5 Humanleukocyteantigenandorgantransplantation 317 complications 367 xii CONTENTS 21.3 TheidentificationoftheNOD2gene 374 24. Molecular mechanisms in cancer 21.4 NOD2andinnateimmunity 375 susceptibility—lessons from inherited cancers 423 21.5 Majorhistocompatibilitycomplex(6p21) 377 SHIRLEYV.HODGSON 21.6 Thecausativegenomevariantsandfunctional implications 378 24.1 Introduction 423 21.7 Autophagy 379 24.2 Inheritedandfamilialcancer 423 21.8 Adaptiveimmunesystem 379 24.3 Oncogenesandtumorsuppressorgenes 424 21.9 Mucosalbarrierfunction 379 24.4 DNArepairgenes 424 21.10 Theparallelsandparadoxeswithotherdiseases 380 24.5 Cancerfamilysyndromes 425 21.11 Clinicalimplicationsandtranslation 380 24.6 Geneticimprintingandcancer 426 21.12 Conclusion 381 24.7 Complexcancergenomics 427 References 381 24.8 Inheritedsusceptibilitytoleukemia 427 Furtherreading 388 24.9 Tumormarkersincirculatingblood 430 24.10 Geneticcounselingforinheritedcancer 22. Molecular biology of acute and chronic susceptibility 430 24.11 Diagnosticandpredictivegenetictesting inflammation 389 forcancer 431 DHAVENDRAKUMAR References 434 Furtherreading 436 22.1 Introduction 389 22.2 Molecularpathologyofacuteinflammation (sepsisandtrauma) 390 25. Clinical molecular nephrology—acute 22.3 Molecularpathologyofchronicinflammation 391 kidney injury and chronic kidney disease 437 22.4 Age-associatedchronicinflammation 392 SHIVARAMHEGDE 22.5 Moleculardiagnosisandtreatmentofchronic inflammatorydiseases 394 25.1 Introduction 437 22.6 Summary 400 25.2 Acutekidneyinjury 437 Acknowledgmentsanddisclaimer 401 25.3 Chronickidneydisease 438 References 401 25.4 Clinicalrenalgenomicmedicine 440 25.5 Molecularbasisofkidneytransplantation 442 25.6 Conclusion 442 23. Molecular basis of susceptibility and References 443 protection from microbial infections 403 RASHIDMERCHANT,PEZADDOCTORAND 26. Molecular basis of chronic AMIVARAIYA neurodegeneration 447 23.1 Introduction 403 MEGHAAGRAWAL 23.2 Understandinghostgeneticvariationofsusceptibility toinfectiousdisease 404 26.1 Introduction 447 23.3 Clinicalrelevanceofhumanleukocyteantigengene 26.2 Neurodegenerativediseaseclinicalcasestudiesand variantsinHBVinfection 405 molecularsystemsunderpinningtheclinicalscenario 448 23.4 Humanleukocyteantigengenevariantsand 26.3 Molecularpathologyofneurodegenerativediseases 453 susceptibilityandpersistenceofHBVinfection 406 26.4 Applicationofmoleculardiagnosticsin 23.5 Immunogeneticsandmicrobialinfection 407 neurodegeneration 456 23.6 Hostgeneticsusceptibilitytohuman 26.5 Summary 458 papillomavirusinfectionanddevelopment References 459 ofcervicalcancer 408 23.7 HostgeneticsofEpstein(cid:1)Barrinfection 409 23.8 Dengueviralinfection 410 27. Molecular basis of movement disorders 461 23.9 Geneticsusceptibilityofhumanstohantavirus CLAIREMacIVER,DAFYDDMORGANANDKATHRYNJ.PEALL infection 411 23.10 Hostfactorsandgeneticsusceptibilitytointracellular 27.1 Introduction 461 bacteria 412 27.2 Parkinson’sdisease 461 23.11 Hostgeneticsusceptibilityandprotectionfromfungal 27.3 Dystonia 464 infections 415 27.4 Ataxia 472 23.12 Malaria 417 27.5 Ataxia:keylearningpoints 480 23.13 Geneticsofsusceptibilitytoenteralpathogens 419 27.6 Othermovementdisorders 480 23.14 Conclusion 420 27.7 Conclusion 483 References 420 References 483
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