HUMAN REPRODUCTIVE GENETICS HUMAN REPRODUCTIVE GENETICS EMERGING TECHNOLOGIES AND CLINICAL APPLICATIONS Editedby Juan A. Garc´ıa-Velasco ReyJuanCarlosUniversity,Madrid,Spain IVIRMAMadrid,Madrid,Spain Emre Seli YaleUniversity,NewHaven,CT,UnitedStates ChiefScientificOfficer,IVIRMAGlobal,BaskingRidge,NJ,UnitedStates AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UnitedKingdom 525BStreet,Suite1650,SanDiego,CA92101,UnitedStates 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom Copyright©2020ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronicormechanical,includingphoto- copying,recording,oranyinformationstorageandretrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhow toseekpermission,furtherinformationaboutthePublisher’spermissionspoliciesandourarrangementswithorganizationssuchas theCopyrightClearanceCenterandtheCopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher(otherthanasmaybenoted herein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroadenourunderstanding, changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusinganyinformation, methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirown safetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliabilityforanyinjury and/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,orfromanyuseoroperationofany methods,products,instructions,orideascontainedinthematerialherein. BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-PublicationData AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-816561-4 ForInformationonallAcademicPresspublications visitourwebsiteathttps://www.elsevier.com/books-and-journals Publisher:StacyMasucci AcquisitionsEditor:TariBroderick EditorialProjectManager:PatGonzalez ProductionProjectManager:SwapnaSrinivasan CoverDesigner:MilesHitchen TypesetbyMPSLimited,Chennai,India Contents List of contributors ix 4. Molecular biology approaches utilized in About the editors xi preimplantation genetics: real-time PCR, microarrays, next-generation sequencing, Preface xiii karyomapping, and others A ALMUDENADEVESA-PEIRO´,JOSEFAMARI´ASA´NCHEZ- REYESANDPATRICIADI´AZ-GIMENO FUNDAMENTALS OF Theembryofactor:preimplantationgenetictesting GENETICS techniquesforembryoselectionagainst chromosomalabnormalitiesandmonogenic disorders 49 1. Basic genetics: mitosis, meiosis, Theendometrialfactor:geneexpressiondiagnostictools chromosomes, DNA, RNA, and beyond toassessendometrialreceptivity 60 Generalconclusion 63 AMANDAN.KALLEN References 64 Furtherreading 67 Introduction 3 References 15 5. Epigenetics and imprinting in assisted 2. Identification of genetic causes of reproduction gynecologic disorders DIEGOMARINANDEMRESELI ALEXANDERKOTLYARANDMARIAD.LALIOTI Introduction 69 Molecularmechanismsofepigeneticregulation 70 Introduction 17 Epigeneticsofaging 75 TheHumanGenomeProject,Mendelianandcomplex Aspecialaspectofepigenetics:imprinting 78 geneticinheritance 17 Assistedreproductivetreatmentandtheepigenome 79 Differencebetweenmutationsandpolymorphisms 18 Summaryandconclusions 80 Approachesforidentifyingthegeneticcauseofa References 81 disorder 18 Furtherreading 86 Summary 28 References 28 B 3. Cytogenetics techniques CLINICAL SCENARIOS INMACULADACAMPOS-GALINDO Introduction 33 6. The quest for genetic sequence variants Karyogram,karyotype,andidiogram 34 Mostfrequentkaryotypeabnormalities 35 conferring risk of endometriosis Heteromorphisms,polymorphisms,ornormal SUN-WEIGUO variants 39 References 44 Introduction 91 v vi Contents Aprimerongeneticstudiesofcomplexdiseasesanda Conclusionsandclinicalimplications 168 reviewofendometriosisgenetics 94 References 169 Identificationofgenesand/orgeneticvariants: recombination,linkagedisequilibrium,and 11. Genetics of premature ovarian association 98 insufficiency Layersofcomplexity 100 JOSESERNA,ELISAVARELAAND Conclusion 103 JUANA.GARCI´A-VELASCO Acknowledgment 104 References 104 Introduction 173 Prematureovarianinsufficiencyetiology 174 7. Genetics of polycystic ovarian syndrome Technicaladvances 175 Geneticsoftheovarianreserve 175 YVONNEV.LOUWERSANDJOOPS.E.LAVEN Folliculardevelopment 177 Introduction 111 Syndromicprematureovarianinsufficiency 178 Heritability 112 FragileXsyndrome 181 Candidategenestudies 112 Roleoftelomeresinprematureovarian Genome-wideassociationstudies 114 insufficiency 185 Functionalstudies 116 Futurediagnosisandtreatment 187 Conclusion 119 References 187 References 119 Furtherreading 199 12. Prenatal testing 8. Male factor infertility: genetic and epigenetic aspects JOSHUAA.COPEL,KATHERINEKOHARI ANDAUDREYA.MERRIAM BRENTM.HANSONANDJAMESM.HOTALING Aneuploidyscreeningtests 201 Introduction 123 Diagnosticprenatalgenetictesting 213 Geneticaspectsofmaleinfertility 126 Availabletestingmodalities 216 Epigeneticaspectsofmaleinfertility 132 References 219 Implications 137 References 138 13. Expanded carrier screening in reproductive medicine 9. Mitochondrial genetics JEFFREYS.DUNGAN ELPIDAFRAGOULI Principlesofcarrierscreening 224 Introduction 143 Historicperspectives 224 Mitochondrialinheritanceandreplication 144 Otheraspectsoftraditionalethnicity-based Mitochondrialdiseases 145 screening 225 Mitochondriainoocytes 146 Universalscreening 226 Mitochondriainsperm 148 Roleofexpandedcarrierscreening 226 Mitochondriainembryos 149 Mutationscreeningversusgenesequencing 229 Conclusion 152 Genotype(cid:1)phenotypecorrelations 230 References 153 Determinationofresidualrisk 230 Clinicalutilityofexpandedcarrierscreening 231 10. Endometrial receptivity and genetics Optionsforcarriercouples 233 CarrierscreeningforX-linkeddisorders 233 NICKMACKLON Counselingforconsanguineouscouples 234 Introduction 159 Counselingregardingvariantsofuncertain Geneticmarkersofendometrialfunction 159 significance 235 Beyondendometrialreceptivity 162 Gametedonors 235 vii Contents Ethicalargumentsinfavorofexpandedcarrier D screening 236 Practicalargumentsopposingexpandedcarrier REPRODUCTIVE GENETIC screening 236 COUNSELING Genesonexpandedcarrierscreeningpanelswith additionalimplications 236 Identifyingindividualswithtwopathogenic 16. Psychological aspects of reproductive variants 237 genetic screening and diagnoses Conclusion 237 References 238 DOROTHYA.GREENFELD Reproductivegeneticscreening 274 C Preconceptioncarrierscreening 274 Preimplantationgenetictestingformonogenic HOW TO ANALYZE AN EMBRYO defects 275 Preimplantationgenetictestingfor aneuploidy 278 14. Preimplantation genetic testing for Theroleoftheinfertilitycounselor 279 monogenic diseases Conclusions 280 References 280 ANACERVEROANDJULIOMARTI´N Introduction 243 17. Bioethics in human reproduction Indicationsforpreimplantationgenetictestingfor (human reproductive genetics) monogenicdiseases 244 HEIDIMERTESANDGUIDOPENNINGS Technologiesandtestingmethods 247 Simultaneousembryotestingforpreimplantationgenetic Introduction 283 testingformonogenicdiseasesandpreimplantation Preconceptiongenetictesting 283 genetictestingforaneuploidies 250 Preimplantationgenetictesting 286 Limitations 251 Preimplantationgeneticdiagnosis 287 Conclusion 251 Preimplantationgenetictestingforaneuploidy References 252 screening 288 Prenatalgenetictesting 289 15. Futuretechnologies for References 291 preimplantation genetic applications 18. The role of genetic counseling in the NADAKUBIKOVAANDDAGANWELLS infertile patient Preimplantationgenetictesting 255 JOSEPPLA-VICTORI Noninvasivepreimplantationgenetictesting 256 Futureperspectivesinpreimplantationgenetictesting Introduction 295 formonogenicdisease 258 Karyotypealterationsasacauseofinfertility 298 Preimplantationgenetictestingforpolygenic Geneticcounselinginpreimplantationgenetic disease 260 testing 302 Whole-genomesequencingofthepreimplantation Monogeniccausesofinfertility 303 embryo 260 Geneticcounselinginexpandedcarrier Germlinegenomeediting 261 screening 306 Howfararewefrom(safe)clinicalapplicationof Communicationskillsingenetics 307 genomeediting? 262 References 312 Ethicalconsiderationsforgermlinegenomeediting 264 Index 317 References 266 List of contributors Inmaculada Campos-Galindo Igenomix, Valencia, Brent M. Hanson RMA New Jersey, Sidney Spain Kimmel Medical College at Thomas Jefferson AnaCervero Igenomix,Valencia,Spain University,BaskingRidge,NJ,UnitedStates Joshua A. Copel Department of Obstetrics, James M. Hotaling Department of Surgery (cid:1) Urology, University of Utah Center for Gynecology, and Reproductive Sciences, Section Reconstructive Urology and Men’s Health, Salt of Maternal-Fetal Medicine, Yale School of Medicine,NewHaven,CT,UnitedStates LakeCity,UT,UnitedStates Almudena Devesa-Peiro´ Department of Genomic Amanda N. Kallen Department of Obstetrics, Gynecology and Reproductive Sciences, Yale & Systems Reproductive Medicine, IVI-RMA IVI School of Medicine, New Haven, CT, United Foundation, Valencia, Spain; Department of States Pediatrics,ObstetricsandGynaecology,Schoolof Medicine,UniversityofValencia,Valencia,Spain Katherine Kohari Department of Obstetrics, Patricia Dı´az-Gimeno Department of Genomic & Gynecology, and Reproductive Sciences, Section of Maternal-Fetal Medicine, Yale School of Systems Reproductive Medicine, IVI-RMA IVI Medicine,NewHaven,CT,UnitedStates Foundation, Valencia, Spain; Biomedical ResearchInstituteHospitalLaFe,Valencia,Spain Alexander Kotlyar Section of Reproductive Jeffrey S. Dungan Division of Clinical Genetics, Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Department of Obstetrics & Gynecology, Sciences, Yale School of Medicine, Yale Northwestern University Feinberg School of Medicine,Chicago,IL,UnitedStates University,NewHaven,CT,UnitedStates Elpida Fragouli IVI RMA Global, Magdalen Nada Kubikova Nuffield Department of Women’s and Reproductive Health, John Radcliffe Centre, Oxford Science Park, Oxford, United Hospital, University of Oxford, Oxford, United Kingdom;NuffieldDepartmentofObstetricsand Gynaecology, University of Oxford, John Kingdom RadcliffeHospital,Oxford,UnitedKingdom Maria D. Lalioti Department of Translational Juan A. Garcı´a-Velasco IVI Foundation, Madrid, Genomics, Goldfinch Bio, Cambridge, MA, UnitedStates Spain;IVIRMAMadrid,Madrid,Spain;ReyJuan CarlosUniversity,Madrid,Spain Joop S.E. Laven Division of Reproductive Dorothy A. Greenfeld Yale University School of Endocrinology and Infertility, Erasmus University Medical Center, Rotterdam, The Medicine,NewHaven,CT,UnitedStates Netherlands Sun-Wei Guo Shanghai Obstetrics and Yvonne V. Louwers Division of Reproductive Gynecology Hospital, Fudan University, Shanghai, P.R. China; Shanghai Key Laboratory Endocrinology and Infertility, Erasmus University Medical Center, Rotterdam, The of Female Reproductive Endocrine-Related Netherlands Diseases,FudanUniversity,Shanghai,P.R.China ix x Listofcontributors Nick Macklon London Women’s Clinic, London, Josefa Mar´ıa Sa´nchez-Reyes Department of United Kingdom; Zealand University Hospital, Genomic & Systems Reproductive Medicine, IVI- Koege,Denmark RMA IVI Foundation, Valencia, Spain; Diego Marin IVIRMA New Jersey, Basking Ridge, Department of Pediatrics, Obstetrics and Gynaecology, School of Medicine, University of NJ, United States; Thomas Jefferson University, Philadelphia,PA,UnitedStates Valencia,Valencia,Spain JulioMartı´n Igenomix,Valencia,Spain EmreSeli IVIRMANewJersey,BaskingRidge,NJ, United States; Yale School of Medicine, New Audrey A. Merriam Department of Obstetrics, Haven,CT,UnitedStates Gynecology, and Reproductive Sciences, Section Jose Serna IVI RMA Zaragoza, Zaragoza, Spain; of Maternal-Fetal Medicine, Yale School of Medicine,NewHaven,CT,UnitedStates IVIFoundation,Madrid,Spain Heidi Mertes Department of Philosophy and Elisa Varela IVI Foundation, Madrid, Spain; IVI RMAMadrid,Madrid,Spain Moral Science, Bioethics Institute Ghent (BIG), GhentUniversity,Gent,Belgium Dagan Wells Nuffield Department of Women’s Guido Pennings Department of Philosophy and and Reproductive Health, John Radcliffe Moral Science, Bioethics Institute Ghent (BIG), Hospital, University of Oxford, Oxford, United Kingdom; Juno Genetics, Oxford, United GhentUniversity,Gent,Belgium Kingdom Josep Pla-Victori IVI-RMA Global, Barcelona, Catalonia,Spain About the editors JuanA.Garcı´a-Velasco Dr.Garc´ıa-Velasco,MD,PhD,isDirectorofIVIMadrid.HeisalsoaFullProfessorofObstetricsand Gynecology at Rey Juan Carlos University, Madrid, Spain, where he is Director of their Master’s DegreePrograminHumanReproduction.HegraduatedfromUniversityMedicalSchool,Madrid,in 1990andreceivedhisObstetricsandGynecologycertificationfromLaPazHospital,Madrid,in1995. He completed his PhD in Medicine from Autonoma University, Madrid, in 1995 and from 1997 to 1998 he studied at Yale University, New Haven, CT, under a Reproductive Endocrinology and Infertility Fellowship. His main research interests have been in IVF and endometriosis. He is the PrincipalInvestigatorofprojectsfundedbytheMinistryofEducationandMinistryofHealth,Spain, and has received awards from the Spanish Fertility Society, Spanish Society of Obstetrics and Gynecology, and theEuropeanSociety of Human Reproductionand Embryology.Hehas published over 200 peer-reviewed articles as well as 22 book chapters on human reproduction, endometriosis, and difficult cases such as women with hypo- and hyperresponse to ovarianstimulation, and is the author/editorofseveralbooks. EmreSeli Dr. Seli is Professor of Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine and Chief Scientific Officer at IVIRMA Global. He received his medical degree from the University of Istanbul and completed his Residency in Obstetrics and Gynecology at Yale University. His postdoctoral training included a fellowship in Reproductive Endocrinology and Infertility as well as a research fellowship in Molecular Biology, both at Yale University. As a physician-scientist,hisprimaryfocusistounderstandandtreatinfertility.Hislaboratorycharacter- ized the mechanisms regulating translational activation of gene expression in the oocyte. Dr. Seli and his colleagues also made seminal contributions to our understanding of oocyte and embryo competenceinIVFandthepotentialroleofnoninvasivediagnostictechnologiesinthiscontext.Dr. Seli is the recipient of many National Institutes of Health (NIH) and pharmaceutical industry- sponsored research grants as well as numerous awards, including the Ira and Ester Rosenwaks New Investigator Award, American Society for Reproductive Medicine (ASRM), and the President’sAchievementAwardfromtheSocietyforReproductiveInvestigation(SRI). xi