Genetic Disordersand the Fetus

Dedicated to

Laura and KiranFor their love, support and understanding

and to

our grandchildren and children,

Julie, Miranda, and Cody,

who endow life with joy and meaning.

“Make assurance double sure.”Shakespeare, Macbeth

Genetic Disordersand the FetusDiagnosis, Prevention,and TreatmentSEVENTH EDITION

EDITED BY

Aubrey Milunsky MB BCh, DSc, FRCP,FACMG, DCHAdjunct Professor of Obstetrics and GynecologyTufts University School of MedicineFounder and Co-Director, Center for Human GeneticsCambridge, MA, USA

Jeff M. Milunsky MD, FACMGCo-Director, Center for Human GeneticsDirector, Clinical GeneticsSenior Director, Molecular GeneticsCambridge, MA, USA

Copyright © 2016 by Aubrey Milunsky and Jeff Milunsky;Previous editions: © 2010 Aubrey Milunsky and Jeff Milunsky;© 2004, 1998, 1992, 1986, 1979 Aubrey Milunsky

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Cover images: Left-hand image: Glowing DNA strand. Courtesy of Johan Swanepoel/iStockphoto. Middletop two images: Karyotopes. © 2015 Steven M. Carr, Terra Nova Genomics, Inc. Middle bottom compositeimages: Fetal scans. Courtesy of Nadine Girard. See Figure 15.3’s caption for more details. Right-handimage: DNA. Courtesy of Aubrey Milunsky.

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Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xii

1 Genetic Counseling: Preconception, Prenatal, and Perinatal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Aubrey Milunsky and Jeff M. Milunsky

2 Amniocentesis, Chorionic Villus Sampling, and Fetal Blood Sampling . . . . . . . . . . . . . . . . . . . . . . 68Anthony O. Odibo

3 Amniotic Fluid Constituents, Cell Culture, and Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . 98Daniel L. Van Dyke and Aubrey Milunsky

4 Prenatal Diagnosis of Chromosomal Abnormalities through Chorionic Villus Samplingand Amniocentesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178Peter A. Benn

5 Prenatal Diagnosis of Sex Chromosome Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267Jeff M. Milunsky

6 Molecular Cytogenetics and Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313Stuart Schwartz

7 Prenatal Diagnosis and the Spectrum of Involvement from Fragile X Mutations . . . . . . . . . . . . . . 350Randi Hagerman and Paul Hagerman

8 Prenatal Diagnosis by Microarray Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366Joris Robert Vermeesch

9 Molecular Genetics and Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380Aubrey Milunsky, Clinton Baldwin, and Jeff Milunsky

10 Preimplantation Genetic Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419Anver Kuliev and Svetlana Rechitsky

11 Noninvasive Prenatal Screening and Diagnosis Using Cell-free Fetal DNA . . . . . . . . . . . . . . . . . . 453Melissa Hill and Lyn S. Chitty

12 Maternal Serum Screening for Chromosomal Abnormalities and Neural Tube Defects . . . . . . . . 483Howard Cuckle, Eugene Pergament, and Peter Benn

13 Prenatal Diagnosis of Fetal Malformations by Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541Yves G. Ville and Jean-Philippe Bault

v

vi Contents

14 Prenatal Diagnosis and Management of Abnormal Fetal Development in the ThirdTrimester of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599Roland Axt-Fliedner and Aline Wolter

15 Prenatal Diagnosis by Fetal Magnetic Resonance Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660Nadine Girard and Kathia Chaumoitre

16 Prenatal Diagnosis of Skeletal Dysplasias and Connective Tissue Disorders . . . . . . . . . . . . . . . . . . 681Andrea Superti-Furga and Sheila Unger

17 Prenatal Diagnosis of Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700Wayne W. Grody

18 Prenatal Diagnosis of the Hemoglobinopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718John M. Old

19 Prenatal Diagnosis of Primary Immunodeficiency Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755Jennifer M. Puck

20 Prenatal Diagnosis of Disorders of Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773Steven Humphries, Sara Mole, and Bryan Winchester

21 Prenatal Diagnosis of the Peroxisomal and Mitochondrial Fatty AcidOxidation Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 838Ronald J.A. Wanders

22 Prenatal Diagnosis of the Mucopolysaccharidoses and Postnatal EnzymeReplacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857John J. Hopwood

23 Disorders of Metabolism of Amino Acids and Related Compounds . . . . . . . . . . . . . . . . . . . . . . . . . 877Georgianne L. Arnold and Jerry Vockley

24 Prenatal Diagnosis of Disorders of Carbohydrate Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903Deeksha Sarihyan Bali, Stephanie Austin, and Yuan-Tsong Chen

25 Prenatal Diagnosis of Miscellaneous Biochemical Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927David S. Rosenblatt and David Watkins

26 Prenatal Diagnosis of Fetal Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942Yves G. Ville and Marianne Leruez-Ville

27 Fetal Medical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976Phyllis W. Speiser and Aubrey Milunsky

28 Fetal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989Benjamin A. Keller, Shinjiro Hirose, and Diana L. Farmer

29 Induced Abortion for Genetic Indications: Techniques and Complications . . . . . . . . . . . . . . . . . . 1011Lee P. Shulman

30 Molecular Aspects of Placental Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031Wendy P. Robinson and Deborah E. McFadden

31 Grief after Perinatal Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048Anette Kersting and Michaela Nagl

Contents vii

32 Medicolegal Aspects of Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063Ellen Wright Clayton

33 Prenatal and Preimplantation Diagnosis: International Policy Perspectives . . . . . . . . . . . . . . . . . . 1091Minh Thu Minh Nguyen and Bartha Maria Knoppers

34 Ethical Issues in the Diagnosis and Management of Genetic Disorders in the Fetus . . . . . . . . . . . 1106Frank A. Chervenak and Laurence B. McCullough

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131

A color plate section falls between pages 624 and 625.

Preface

The seductive nature of novel technologies thatintroduce new preventive, diagnostic and thera-peutic avenues is at once appealing, exciting andinherently risky. A faster, sleeker, cheaper ship mayflounder on the hidden rocks of uncertainty. Theprimary destination may be reached with greaterspeed and efficiency, only to end accountable forinitially unforeseen damage or loss. In the contextof prenatal genetic diagnosis, as for all fields ofmedicine, abiding by the overriding principle ofprimum non nocere, remains paramount. This isespecially pertinent given the unique responsibilityof simultaneous caring for mother and fetus. Inthis compact there is the challenge to help andnot to harm, given the complexity of genomeinterpretation.

The new and exciting developments in non-invasive prenatal testing, reflected in this volume,make prenatal detection of certain commonchromosomal disorders and less common (orrare) monogenic diseases, available to all pregnantwomen. The inherent limitations of these inno-vations need careful explanations and informedconsent to avoid a patient thinking that all geneticdisorders have been excluded, when a screeningnegative has been provided. The principles andprerequisites for prenatal and preconceptiongenetic counseling with special reference to poten-tial pitfalls and limitations, open this text with anextensive, heavily referenced discussion.

Rapid progress in the application of moleculargenetics methods to prenatal diagnosis, includingfetal microarray analysis, whole exome sequencing,next generation sequencing and whole genomesequencing, have outstripped the knowledge baserequired to provide consistent reliable interpreta-tion for a DNA diagnostic test result. Witness thespawning of terms, such as, ‘variations of uncertain

significance’, that inevitably create unwanted anx-ieties, but frequently accompany DNA sequencingreports. Worse still, clear delineation of normalvariation or polymorphisms remains far fromcomplete, and is compounded by the difficulty ofdetermining the pathogenicity of variants. Com-mon anticipated complications of these sequencingtechnologies include depth of coverage, regions ofhigh GC content, mosaicism, DNA contamination,digenic inheritance, locus heterogeneity, and false-positive and false-negative results. Waiting in thewings is the management and counseling challengefollowing determination of a clinically significantincidental (secondary) finding on fetal DNA analy-sis of a disorder that predictably would manifest inadulthood. Indeed, increasingly, prenatal diagnosisfor serious/fatal adult-onset diseases is beingpursued (e.g., breast cancer).

This edition is fully up-to-date and replete withauthoritative guidance about the applications ofmolecular genetics to the vast panoply of genomicdisorders in the context of prenatal diagnosis andpreimplantation genetic diagnosis (PGD). Detailedconsideration is devoted to the prenatal diagnosisof monogenic disorders, now more approachablethan previously for the extensively described bio-chemical genetic diseases that include the lipid andcarbohydrate storage disorders, the mucopolysac-charidoses, the aminoacidopathies, peroxisomaland mitochondrial fatty acid oxidation, and folateand cobalamin disorders.

Notwithstanding the remarkable applications toprenatal diagnosis and PGD following discoveryof thousands of culprit genes and their mutations,original pillars of prenatal diagnosis remain fun-damental and require full comprehension, evenwhen molecular diagnosis is pursued. Hence, verydetailed and superbly referenced chapters delineate

ix

x Preface

the necessary current knowledge-base of prenataldiagnosis procedures (amniocentesis, chorionicvillus sampling, periumbilical blood sampling,amniotic fluid constituents and cell culture), chro-mosomal and FISH analysis, neural tube defectdetection, and the very important microarrayanalysis.

Critical progress and analysis is also reflectedin detailed chapters on the prenatal diagnosisof the Fragile-X syndrome, cystic fibrosis, thehemoglobinopathies, the immunodeficiency disor-ders, and fetal infection. Whereas maternal serummultianalyte screening has for decades dominatedthe prenatal detection of neural tube defects andchromosomal abnormalities, refinements in fetalimaging for these and other fetal structural defectshave assumed key roles. The twin complemen-tary diagnostic roles of fetal ultrasound and mag-netic resonance imaging in the first, second andthird trimesters of pregnancy are critically assessedby internationally recognized experts. Emphasis isgiven to the concomitant imaging and moleculardiagnostics, especially for the skeletal dysplasias.The role of fetal medical and surgical therapy hasexpanded and for specific disorders demands greatskill and expertise.

For the first time this edition focuses on newmolecular advances that inform about placentaldevelopment and the implications for fetal health.Another new addition is the moving and insight-ful analysis concerning the psychology of prena-tal and perinatal grief. Understanding the devel-opment and utility of established approaches andnovel technologies to prenatal diagnosis and PGD,invariably antedates ethical and legal applicationsand implications, and the evolution of public policy.Key authoritative chapters on ethics, law, and pub-lic policy reflect new thought and developments inthese critical, non-static arenas.

The discerning reader in search of accurate andreliable information would welcome a source that

reliably dispenses evidence-based facts embellishedby knowledge, experience and wisdom. This pre-cious distillate, tinctured with recommendationsand guidance born of long experience, is not attain-able by the most avid electronic voyeur. Siftingthrough mountains of unfiltered, irrelevant, unreli-able or misleading information, electronic searchessimply spawn reams of paper, mostly lacking crit-ical analysis of the subject in question. At best,authors will describe “limitations” in their studies,while awaiting guidance from their clinical collegesor societies, which often takes years.

Fortunately, this volume, a major repository offacts about prenatal diagnosis, provides a criti-cal analysis and synthesis of established and newknowledge based on the long experience of the con-tributing authorities in their respective fields. Inaddition, a broad international perspective is pre-sented with contributions from recognized expertsin 10 countries. The guidance provided and theinsights and perspectives of these authors make thisvolume a valuable and indispensable resource for allthose whose focus is securing fetal health throughprenatal diagnosis.

This text is very heavily referenced, replete withevidence-based guidance, and reflective of the life-time experience and wisdom of the authors. Thisedition encompasses 158 tables, 108 figures, includ-ing 14 color plates, and about 9,000 references. Avaluable index will enrich the reader’s search forspecific information. It is our fervent hope that theprogress mirrored in this volume will help prospec-tive parents recognize their reproductive risks andoptions, and reassure many that they can avoid hav-ing children with serious or lethal genetic disorders.Indeed, parents initially unaware of their risks mayalso benefit from the remarkable advances in pre-natal and preimplantation genetic diagnosis.

Aubrey Milunsky and Jeff M. MilunskyCambridge

Acknowledgements

This seventh edition marks the 36th year of this textand reflects the continuing remarkable advancesmade in achieving accurate prenatal diagnoses.The first book on this subject (The PrenatalDiagnosis of Hereditary Disease) was publishedsome 42 years ago (by AM). The distillation ofaccrued biological, technological, ethical and legalknowledge has graced these pages and enrichedthe reference value of these editions. The wisdom,insight, perspective, expertise and knowledge ofcontributing authors has made these volumes avaluable and authoritative text. Moreover, theseauthors have again provided an international per-spective, this edition having contributions from 19countries.

Knowledge in human genetics and maternal–fetal medicine has demanded up to date infor-mation, guidance and expertise in each volume.This has been achieved only by the willingness ofinternationally recognized authoritative authors

who have taken the time to share their knowledge,experience, and wisdom. For this we are mostappreciative.

We are also grateful and indebted to our friendsand colleagues who have died and who were con-tributing authors to earlier editions. We rememberthem with pride and sadness: David J. H. Brock,Ph.D., Jacob A. Canick, Ph.D., Louis Dalliaire,M.D., Ph.D., Sherman Elias, M.D., John C. FletcherPh.D., Albert B. Gerbie, M.D., Leonard A. Herzen-berg, Ph.D., Mary Z. Pelias, Ph.D., J.D., ArthurRobinson, M.D., Margery W. Shaw, M.D., J.D.,Irving Umansky, M.D., Yury Verlinsky, Ph.D., andDorothy C. Wertz, Ph.D.

It is likely that we are unaware of the passing of afew authors, and regret their omission. We remaineternally grateful to all.

Aubrey MilunskyJeff Milunsky

xi

List of Contributors

Georgianne L. Arnold, MDProfessor of PediatricsUniversity of Pittsburgh School of MedicineClinical Director, Division of Medical GeneticsChildren’s Hospital PittsburghPittsburgh, PA, USA

Stephanie Austin, MS, MA, CGCGenetic CounsellorDuke University Medical CenterDurham, NC, USA

Roland M. Axt-Fliedner, MD, PhDProfessor of Obstetrics and GynecologyJustus-Liebig-UniversityHeadDivision of Prenatal Medicine and Fetal TherapyUniversity HospitalGießen, Germany

Clinton Baldwin, PhDDirectorMolecular Genetics ResearchCenter for Human Genetics, Inc.Cambridge, MA, USA

Deeksha S. Bali, PhD, FACMGProfessor of PediatricsLaboratory DirectorDivision of Medical GeneticsDuke University Medical CenterDurham, NC, USA

Jean-Philippe Bault, MDConsultant in ObstetricsObstetrics DepartmentHopital BicetreUniversity Hospital Paris-SudCentre Hospitalier Intercommunal de Poissy-St. Germain

en LayePoissy, France

Peter A. Benn, MSc, PhD, FACMG, DScProfessorDepartments of Genetics and Genome SciencesPediatrics and Laboratory MedicineDirectorHuman Genetics LaboratoriesUniversity of Connecticut Health CenterFarmington, CT, USA

Kathia Chaumoitre, MD, PhDDepartment of RadiologyTimone HospitalAix-Marseille UniversityMarseille, France

Yuan-Tsong Chen, MD, PhDProfessor of Pediatrics and GeneticsDuke University Medical CenterDurham, NC, USAInstitute of Biomedical SciencesAcademia SinicaTaiwan

Frank A. Chervenak, MDGiven Foundation Professor and ChairmanDepartment of Obstetrics and GynecologyObstetrician and Gynecologist-in-ChiefWeill Cornell Medical CenterNew York Presbyterian HospitalNew York, NY, USA

Lyn S. Chitty, PhD, MB, BS, MRCOGProfessor of Genetics and Fetal MedicineUCL Institute of Child HealthGreat Ormond Street Hospital for Children andUniversity College London Hospital NHS FoundationTrustsLondon, UK

Ellen Wright Clayton, MD, JDCraig-Weaver Professor of PediatricsProfessor of LawCo-FounderCenter for Biomedical Ethics and Society

xii

List of Contributors xiii

Vanderbilt UniversityNashville, TN, USA

Howard Cuckle, MSc, DPhilAdjunct Professor, Obstetrics and GynecologyColumbia UniversityNew York, NY, USA

Diana L. Farmer, MD, FACS, FRCSPearl Stamps Stewart Professor and ChairDepartment of SurgeryUC Davis School of MedicineSurgeon-in-ChiefUC Davis Children’s HospitalUC Davis Health SystemSacramento, CA, USA

Nadine Girard, MD, PhDProfessor of NeuroradiologyCentre de Resonance Magnetique Biologique et

MedicaleCentre National de la Recherche ScientifiqueFaculte de Medicine la TimoneUniversite de La MediterraneeHead of NeuroradiologyTimone HospitalAix-Marseille UniversityMarseille, France

Wayne Grody, MD, PhDProfessorDivisions of Medical Genetics and Molecular DiagnosticsDepartments of Pathology and Laboratory Medicine

Pediatrics, and Human GeneticsUCLA School of MedicineUCLA Institute for Society and GeneticsDirectorMolecular Diagnostic Laboratories and Clinical Genomics

CenterUCLA Medical CenterLos Angeles, CA, USA

Paul J. Hagerman, MD, PhDDistinguished ProfessorDepartment of Biochemistry and Molecular MedicineSchool of MedicineUC Davis Health SystemSacramento, CA, USA

Randi J. Hagerman, MDMedical DirectorMIND InstituteDistinguished Professor of PediatricsEndowed Chair in Fragile X ResearchUC Davis Health SystemSacramento, CA, USA

Melissa Hill, BSc, PhDSenior ResearcherNorth East Thames Regional Genetics ServiceGreat Ormond Street Hospital for Children NHS

Foundation TrustLondon, UK

Shijiro Hirose, MDAssociate Professor and ChiefDivision of Pediatric GeneralThoracic and Fetal SurgeryDepartment of SurgeryUC Davis School of MedicineSacramento, CA, USA

John J. Hopwood, PhDProfessor and DirectorLysosomal Diseases Research UnitSouth Australian Health and Medical Research InstituteAdelaide, Australia

Steven E. Humphries, PhDProfessor of Cardiovascular GeneticsCentre for Cardiovascular GeneticsInstitute of Cardiovascular ScienceUniversity College LondonLondon, UK

Benjamin A. Keller, MDDepartment of SurgeryUC Davis School of MedicineUC Davis Health SystemSacramento, CA, USA

Anette Kersting, MDProfessorDepartment of Psychosomatic MedicineDirectorClinic for Psychosomatic MedicineUniversity of LeipzigLeipzig, Germany

Bartha M. Knoppers, PhD, OC, OQCanada Research Chair in Law and MedicineDirectorCentre of Genomics and PolicyFaculty of MedicineDepartment of Human GeneticsMcGill UniversityMontreal, Quebec, Canada

Anver Kuliev, MD, PhDDirector of ResearchReproductive Genetics InnovationsNorthbrook, IL, USA

xiv List of Contributors

Marianne Leruez-Ville, MD, PhDConsultant in Medical VirologyNational Reference Laboratory for Congenital

Cytomegalovirus InfectionsHopital Necker-Enfants-MaladesUniversite Paris DecartesParis, France

Laurence B. McCullough, PhDDalton Tomlin ChairMedical Ethics and Health PolicyCenter for Medical Ethics and Health PolicyBaylor College of MedicineHouston, TX, USA

Deborah E. McFadden, MD, FRCPCHead and Medical DirectorDepartment of Pathology and Laboratory MedicineChildren’s & Women’s Hospitals of British ColumbiaClinical ProfessorDepartment of Pathology and Laboratory MedicineUniversity of British ColumbiaVancouver, BC, Canada

Aubrey Milunsky, MD BCh, DSc, FRCP,

FACMG, DCHProfessor of Obstetrics and GynecologyTufts University School of MedicineFounder and Co-DirectorCenter for Human GeneticsCambridge, MA, USA

Jeff M. Milunsky, MD, FACMGCo-DirectorCenter for Human GeneticsDirectorClinical GeneticsSenior DirectorMolecular GeneticsCambridge, MA, USA

Sara Mole, PhDReader in Molecular Cell BiologyUCL Institute of Child HealthMRC Laboratory of Molecular Cell BiologyGenetics and Epigenetics in Health and Disease SectionGenetics and Genomics Medicine ProgrammeDepartment of GeneticsEvolution and EnvironmentUniversity College LondonLondon, UK

Michaela Nagl, PhDDepartment of Psychosomatic Medicine

and Psychotherapy

University of LeipzigLeipzip, Germany

Minh Thu Minh Nguyen, LLM, LLB, BScResearch AssociateCentre of Genomics and PolicyMcGill UniversityMontreal, Quebec, Canada

Anthony O. Odibo, MD, MSCEProfessorMaternal Fetal MedicineDepartment of Obstetrics and GynecologyUniversity of South FloridaTampa, FL, USA

John M. Old, PhD, FRCPathConsultant Clinical Scientist and Reader

in HaematologyNational HaemoglobinopathyReference Laboratory HaematologyJohn Radcliffe HospitalOxford University Hospitals NHS TrustOxford, UK

Eugene Pergament, MD, PhDProfessor of Clinical Obstetrics and GynecologyFeinberg School of Medicine of Northwestern UniversityNorthwestern Reproductive GeneticsChicago, IL, USA

Jennifer M. Puck, MDProfessor of PediatricsUCSF Smith Cardiovascular Research InstituteSan Francisco, CA, USA

Svetlana Rechitsky, PhDPresidentReproductive Genetic InnovationsNorthbrook, IL, USA

Wendy P. Robinson, PhDProfessor, Department of Medical GeneticsUniversity of British Columbia; and Senior ScientistChild and Family Research InstituteVancouver, BC, Canada

David S. Rosenblatt, MDCMDodd Q. Chu and Family Chair in Medical GeneticsProfessorDepartments of Human GeneticsMedicine, Pediatrics, and BiologyFaculties of Medicine and ScienceMcGill UniversityMontreal, Quebec, Canada

List of Contributors xv

Stuart Schwartz, PhDStrategic DirectorCytogeneticsLaboratory Corporation of America ® HoldingsResearch Triangle Park, NC, USA

Lee P. Shulman, MDAnna Ross Lapham Professor in Obstetrics and GynecologyChiefDivision of Clinical GeneticsDirector, Northwestern Ovarian Cancer Early Detection

and Prevention ProgramCo-DirectorCancer Genetics ProgramRobert S. Lurie Comprehensive Cancer CenterFeinberg School of Medicine of Northwestern UniversityMedical DirectorInsight Medical GeneticsAdjunct ProfessorDepartment of Medicinal Chemistry and PharmacognosyUniversity of Illinois at Chicago College of PharmacyChicago, IL, USA

Phyllis W. Speiser, MDProfessorDepartment of PediatricsNew York University School of MedicineChiefDivision of Pediatric EndocrinologySchneider Children’s HospitalNorth Shore–LIJ Health SystemNew Hyde Park, NY, USA

Andrea Superti-Furga, MDProfessor of PediatricsUniversity of Lausanne and ChairDepartment of PediatricsLausanne University HospitalLausanne, Switzerland

Sheila Unger, MD, FRCPC, Privat-DocentMedical Genetics ServiceLausanne University HospitalLausanne, Switzerland

Daniel L. Van Dyke, PhDProfessor of Laboratory Medicine and PathologyMayo Medical School and Mayo ClinicCytogenetics LaboratoryRochester, MN, USA

Joris Robert Vermeesch, PhDProfessor of Molecular Cytogenetics and Genome ResearchHead of Constitutional CytogeneticsCoordinator of Genomics Core

Center for Human GeneticsKatholieke Universiteit LeuvenLeuven, Belguim

Yves G. Ville, MDProfessor of Obstetrics and GynecologyHopital Necker-Enfants-MaladesUniversite Paris DecartesParis, France

Gerard Vockley, MD, PhDChief, Division of Medical GeneticsChildren’s Hospital of PittsburghProfessor of Pediatrics; Professor of Human GeneticsUniversity of Pittsburgh School of MedicineUniversity of Pittsburgh Graduate School of Public HealthPittsburgh, PA, USA

Ronald J.A. WandersUniversity of Amsterdam, Academic Medical CenterDepartments of Clinical Chemistry and PediatricsEmma Children’s HospitalLaboratory of Genetic Metabolic DiseasesAmsterdam, the Netherlands

David Watkins, PhDResearch AssociateDepartment of Human GeneticsMcGill UniversityScientistDepartment of Medical GeneticsMcGill University Health CentreMontreal, Quebec, Canada

Bryan G. Winchester, MA, PhDEmeritus Professor of BiochemistryULC Institute of Child HealthUniversity College LondonLondon, UK

Aline Wolter, MDJustus-Liebig-University, GießenDepartment of Obstetrics and GynecologyDivision of Prenatal Medicine and Fetal TherapyUniversity HospitalGießen, Germany

1 Genetic Counseling:Preconception, Prenatal,and PerinatalAubrey Milunsky1,2 and Jeff M. Milunsky11Center for Human Genetics, Cambridge, MA, USA2Tufts University School of Medicine, Cambridge, MA, USA

Clinical cognizance of the veritable explosion inthe knowledge of the human genome is morevital than ever. Precise identification of genes andtheir pathogenic mutations has injected an urgencyamong care providers to become aware of therapidly escalating opportunities parents have toavoid having offspring with serious or fatal geneticdisorders. For any health or life-threatening geneticdisorder, prenatal diagnosis (or even preimplanta-tion genetic diagnosis) has become a viable option,and should be offered. Even adult-onset malignant,neurodegenerative, cardiovascular and other seri-ous systemic disorders now feature in the indica-tions, not only for presymptomatic or predictivediagnosis, but for prenatal diagnosis.

Given the wide scope of clinical genetics in allmedical specialties, the need for clinicians to conferand refer has never been greater. The coalescence ofadvances in molecular genetics, fetal imaging andnoninvasive prenatal screening, has culminated inthe provision of new opportunities for the preven-tion or avoidance of genetic disorders and congen-ital malformations.

In context, women at risk for having progenywith abnormalities expect to be informed abouttheir odds and options, optimally during precon-ception counseling. Their concerns are serious,

given the significant contribution of genetic dis-orders to morbidity and mortality in children andadults.

Incidence, prevalence and burdenof genetic disorders andcongenital malformations

An estimated 7.9 million infants worldwide areborn each year with a major congenital malfor-mation.1 Over 7,000 rare genetic disorders areknown,2–7 with about 1 in 12 individuals affected,aware or unaware. More than 3,412 genes withphenotype-causing mutations have been identi-fied.4 Severe intellectual disability is considered tobe largely genetic in origin8, 9 and is estimated tooccur in 0.5 percent of newborns.10 The EuropeanOrganization for Rare Diseases maintained thatabout 30 percent of all patients with a rare diseasedied before the age of 5 years.11 In the United Statesin 2010, congenital malformations, deformationsand chromosomal abnormalities accounted forthe most infant deaths – 5,107 (20.8 percent) outof 24,586 – in any category of causation.12 Manyfactors influence efforts to accurately determinethe incidence or prevalence of congenital anoma-lies or genetic disorders. Box 1.1 encompasses the

Genetic Disorders and the Fetus: Diagnosis, Prevention, and Treatment, Seventh Edition.Edited by Aubrey Milunsky and Jeff M. Milunsky.© 2016 by Aubrey Milunsky and Jeff Milunsky. Published 2016 by John Wiley & Sons, Inc.

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2 Genetic Disorders and the Fetus

majority of known etiologic categories, discussedbelow, which help explain sometimes strikingdifferences among major studies. It is almostimpossible to account for all these potentiallyconfounding factors in a study and rarely has anyone study come close.

Incidence and prevalenceEstimates of aneuploidy in oocytes and spermreach 25 percent and 3–4 percent, respectively.13,14

Not surprisingly, then, about one in 13 concep-tions results in a chromosomally abnormal con-ceptus,15 while about 50 percent of first-trimesterspontaneous abortions are associated with chro-mosomal anomalies.16 A study of blastocysts haverevealed that 56.6 percent were aneuploid. More-over, these blastocysts produced in vitro fromwomen of advanced maternal age also revealedmosaicism in 69.2 percent.17 Similar results havebeen reported by others.18 Clinically significantchromosomal defects occur in 0.65 percent of allbirths; an additional 0.2 percent of babies are bornwith balanced structural chromosome rearrange-ments that have implications for reproduction laterin life. Between 5.6 and 11.5 percent of stillbirthsand neonatal deaths have chromosomal defects.19

Congenital malformations with obvious struc-tural defects are found in about 2 percent of allbirths.20 This was the figure in Spain among710,815 livebirths,21 with 2.25 percent in Liberia,22

2.03 percent in India,23 and 2.53 percent amongnewborn males in Norway.24 The Mainz BirthDefects Registry in Germany in the 1990–1998period reported a 6.9 percent frequency of majormalformations among 30,940 livebirths, still-births and abortions.25 Pooled data from 12US population-based birth defects surveillancesystems, which included 13.5 million livebirths(1999–2007), revealed that American Indians/Alaska natives had a ≥50 percent greater preva-lence for seven congenital malformations (anotiaor microtia, cleft lip, trisomy 18, encephalocele,limb-reduction defect).26 Factors that had animpact on the incidence/prevalence of congenitalmalformations are discussed below.

Over 22,700 entries for genetic disorders andtraits have been catalogued.4 Estimates based on1 million consecutive livebirths in Canada sug-gested a monogenic disease in 3.6 in 1,000, con-

Table 1.1 The frequencies of genetic disorders in 1,169,873

births, 1952–198327

Rate per

million Total

Category livebirths births (%)

A

Dominant 1,395.4 0.14

Recessive 1,665.3 0.17

X-linked 532.4 0.05

Chromosomal 1,845.4 0.18

Multifactorial 46,582.6 4.64

Genetic unknown 1,164.2 0.12

Total 53,175.3 5.32a

B

All congenital anomalies 740–759b 52,808.2 5.28

Congenital anomalies with genetic

etiology (included in section A)

26,584.2 2.66

C

Disorders in section A plus those

congenital anomalies not

already included

79,399.3 7.94

Notes: aSum is not exact owing to rounding. bInternational

Classification of Disease numbers.

sisting of autosomal dominant (1.4 in 1,000),autosomal recessive (1.7 in 1,000) and X-linked-recessive disorders (0.5 in 1,000).27 Polygenic dis-orders occurred at a rate of 46.4 in 1,000 (Table 1.1).

At least 3–4 percent of all births are associatedwith a major congenital defect, intellectual dis-ability or a genetic disorder, a rate that doubles by7–8 years of age, given later appearing and/or laterdiagnosed genetic disorders.28, 29 If all congenitaldefects are considered, Baird et al.27 estimatedthat 7.9 percent of liveborn individuals have sometype of genetic disorder by about 25 years of age.These estimates are likely to be very low given, forexample, the frequency of undetected defects suchas bicuspid aortic valves that occur in 1–2 percentof the population.30 The bicuspid aortic valve is themost common congenital cardiac malformationand in the final analysis may cause higher mortal-ity and morbidity rates than all other congenitalcardiac defects.31 Mitral valve prolapse affects 2–3percent of the general population, involving morethan 176 million people worldwide.32 A Canadianstudy of 107,559 patients with congenital heartdisease reported a prevalence of 8.21 per 1,000

CHAPTER 1 Genetic Counseling: Preconception, Prenatal, and Perinatal 3

Box 1.1 Factors that influence estimates of the incidence or prevalence inthe newborn of a congenital malformation (CM) or genetic disorder

Availability and use of expertise in prenataldiagnostic ultrasound

Case selection, bias and ascertainmentConsanguinityDefinitions of major and minor congenital

anomaliesDiagnostic DNA analysisEconomic level in developed or developing worldFamily historyFrequency, inclusion and exclusion of stillbirths,

fetal deaths and elective pregnancy terminationFrequency of certain infectious diseasesHistory of recurrent spontaneous abortionIn vitro fertilizationIncidence and severity of prematurityInfertilityIntracytoplasmic sperm injectionLater manifestation or onset of disorderMaternal ageMaternal alcohol abuseMaternal diabetes and gestational diabetesMaternal dietMaternal epilepsy, lupus erythematosus and other

illnessesMaternal fever or use of hot tub in the first 6 weeks

of pregnancy

Maternal folic acid supplementationMaternal grandmother’s ageMaternal obesityMaternal serum screening for chromosome

abnormalitiesMaternal smokingMaternal specific susceptibility genesMaternal use of medicationMultiple pregnancy rateNecropsyNoninvasive prenatal screeningParent with a congenital abnormality or genetic

disorderPaternal agePrevious affected childPrevious maternal immunization/vaccinationSeason of the yearTraining and expertise in examination of

newbornsUse of chromosomal analysisUse of chromosomal microarrayUse of whole exome sequencingUse of whole genome sequencingUse of death certificatesUse of registry data

livebirths, rising to an overall prevalence of 13.11per 1,000 in adults.33 The authors concluded thatadults now account for some two-thirds of theprevalence of congenital heart disease. Categoricalexamples of factors associated with an increasedrisk of congenital heart disease in the fetus areshown in Box 1.1. A metropolitan Atlanta study(1998–2005) showed an overall prevalence of 81.4per 10,000 for congenital heart disease among398,140 livebirths,35 similar to a Belgium studyof 111,225 live and stillborn infants ≥26 weeksof gestation with an incidence of 0.83 percent,chromosome abnormalities excluded.36 Thesenumbers lead to a significant genetic diseaseburden and have accounted for 28–40 percent ofhospital admissions in North America, Canada andEngland.37, 38 Notwithstanding their frequency,

the causes of about 60 percent of congenitalmalformations remain obscure.39, 40

The availability of prenatal diagnosis and mater-nal serum screening for neural tube defects (NTDs)and Down syndrome (DS) has also affected thebirth frequency of these two most common con-genital defects. One French study of the impact ofprenatal diagnosis over a 21-year period (1979–99) in a well defined population showed a dropof 80 percent in the birth prevalence of DS.41 Alater report from the Paris Registry of Congeni-tal Anomalies (2001–2005) noted a “fairly stableprevalence of DS (7.1 per 10,000 livebirths) overtime.”42 Multiple studies have recorded a reduc-tion in the birth prevalence of NTDs following folicacid supplementation and/or fortification of cerealgrain products with folic acid43–47 (see Chapter 3).

4 Genetic Disorders and the Fetus

However, in Ireland there appears to be an increas-ing incidence of NTDs, almost certainly due toa lack of adherence to periconceptional folic acidsupplementation.48 A Scottish study aimed toassess the impact of prenatal diagnosis on theprevalence of DS from 1980 to 1996. Both birthsand pregnancy terminations were included. Preg-nancy terminations for DS rose from 29 percentto about 60 percent.49 In contrast, the prevalenceof DS noted by the Dutch Paediatric SurveillanceUnit in 2003 was 16 per 10,000 livebirths, exceed-ing earlier reports and thought to reflect an oldermaternal age cohort.50 In the United States, a DSprevalence rate of 13 per 10,000 was found inmetropolitan Atlanta (1979–2003).51

Folic acid supplementation, via tablet or foodfortification, is now well known to reduce the fre-quency of NTDs by up to 70 percent.52, 53 A Cana-dian study focused on the effect of supplementationon the prevalence of open NTDs among 336,963women. The authors reported that the prevalenceof open NTDs declined from 1.13 in 1,000 pregnan-cies before fortification to 0.58 in 1,000 pregnanciesthereafter.54

In a population-based cohort study by theMetropolitan Atlanta Congenital Defects Program,the risk of congenital malformations was assessedamong 264,392 infants with known gestationalages, born between 1989 and 1995. Prematureinfants (< 37 weeks of gestation) were found to bemore than twice as likely to have been born withcongenital malformations than infants at term.55

In a prospective study of infants weighing 401–1,500 g between 1998 and 2007, a congenital mal-formation was noted in 4.8 percent of these verylow birth weight infants. The mean gestational ageoverall was 28 weeks and the mean birth weightwas 1,007 g.56 Twins have long been known tohave an increased rate of congenital anomalies. AUK study of 2,329 twin pregnancies (4,658 twins)and 147,655 singletons revealed an anomaly rateof 405.8 per 10,000 twins versus 238.2 per 10,000singletons (relative risk (RR) 1.7).57 The prevalencerate of anomalies among known monochorionictwins (633.6 per 10,000) was nearly twice that foundin dichorionic twins (343.7 per 10,000) (RR 1.8).

A key study of homozygosity in consan-guineous patients with an autosomal recessivedisease showed that, on average, 11 percent oftheir genomes were homozygous.58 Each affected

individual had 20 homozygous segments exceeding3 cM.

Incidence/prevalence rates of congenital defectsare directly influenced by when and how diagnosesare made. Highlighting the importance of how earlya diagnosis is made after birth, the use of echocar-diography, and the stratification of severity of con-genital heart defects, Hoffman and Kaplan59 clar-ified how different studies reported the incidenceof congenital heart defects varying from 4 in 1,000to 50 in 1,000 livebirths. They reported an inci-dence of moderate and severe forms of congeni-tal heart disease in about 6 in 1,000 livebirths, afigure that would rise to at least 19 in 1,000 live-births if the potentially serious bicuspid aortic valveis included. They noted that if all forms of congeni-tal heart disease (including tiny muscular ventric-ular septal defects) are considered, the incidenceincreases to 75 in 1,000 livebirths.

The frequency of congenital defects is also influ-enced by the presence or absence of such defectsin at least one parent. A Norwegian Medical BirthRegistry population-based cohort study of 486,207males recorded that 12,292 (2.53 percent) had beenborn with a congenital defect.24 Among the off-spring of these affected males, 5.1 percent had acongenital defect, compared with 2.1 percent of off-spring of males without such defects (RR 2.4). Eth-nicity, too, has a bearing on the prevalence of car-diovascular malformations. In a New York Statestudy of 235,230 infants, some 2,303 were bornwith a cardiovascular malformation. The preva-lence among non-Hispanic whites (1.44 percent)was higher than in non-Hispanic blacks (1.28 per-cent).60 However, racial/ethnic disparities clearlyexist for different types of congenital defects.61

Maternal obesity is associated with an increasedrisk of congenital malformations.62–71 The greaterthe maternal body mass index (BMI), the higher therisk, especially for congenital heart defects,67, 68, 70

with significant odds ratios between 2.06–3.5. Ina population-based case-control study, excludingwomen with pre-existing diabetes, Watkins et al.72

compared the risks of selected congenital defectsamong obese women with those of average-weightwomen. They noted significant odds ratios forspina bifida (3.5), omphalocele (3.3), heart defects(2.0), and multiple anomalies (2.0). Our own73, 74

and other studies,75 have pointed in the directionof a prediabetic state or gestational diabetes as the

CHAPTER 1 Genetic Counseling: Preconception, Prenatal, and Perinatal 5

biologic mechanism accounting for the increasedrate of congenital anomalies in the offspringof obese women. In this context, preconceptionbariatric surgery seems not to reduce the risks ofcongenital anomalies.69 It appears that folic acidsupplementation attenuates but does not eliminatethe risk of spina bifida when associated with dia-betes mellitus76 or obesity.77 In contrast, markedlyunderweight women reportedly have a 3.2-foldincreased risk of having offspring with gastroschi-sis,77 in all likelihood due to smoking.78 Indeed, astudy of 173,687 malformed infants and 11.7 mil-lion unaffected controls, when focused on maternalsmoking, yielded significant odds ratios up to 1.5,for a wide range of major congenital malformationsin the offspring of smoking mothers.78 Young nul-liparous women have an increased risk of bearinga child with gastroschisis, those between 12 and 15years of age having a more than fourfold increasedrisk.79

Congenital hypothyroidism is associated with atleast a fourfold increased risk of congenital malfor-mations, and represents yet another factor that mayinfluence incidence/prevalence rates of congenitalanomalies.80 A French study of 129 infants withcongenital hypothyroidism noted that 15.5 percenthad associated congenital anomalies.81 Nine of theinfants had congenital heart defects (6.9 percent).

Women with epilepsy who are taking anticon-vulsant medications have an increased risk of hav-ing offspring with congenital malformations, notedin one study as 2.7-fold greater than those withoutepilepsy.82 The possible reduction of other congen-ital malformations as a result of folic acid supple-mentation remains to be proved (see Chapter 3).

Congenital malformations and infantmorbidity and mortalityThe leading cause of infant death in the UnitedStates in 2011 was congenital malformations, defor-mations and chromosomal abnormalities, account-ing for 20.9 percent of all infant deaths.83 Survivalis clearly dependent on the severity or lethalityof the congenital defect. The Centers for DiseaseControl and Prevention assessed mortality ratesfor infants born with trisomy 13 and trisomy 18.The authors identified 5,515 infants born with tri-somy 13 and 8,750 born with trisomy 18. Themedian age at death for both trisomy 13 and tri-somy 18 was 10 days. Survival to at least 1 year

occurred in 5.6 percent of those born with trisomy13 or trisomy 18.84 A regional study in the Nether-lands noted lethal congenital malformations in 51percent of stillbirths and 70 percent among thosewho died during the neonatal period.85, A Scot-tish study focused on the survival of 6,153 infantswith congenital anomalies up to the age of 5 years,noted the following survival rates: chromosomalanomalies (48 percent), neural tube defects (72 per-cent), respiratory system anomalies (74 percent),congenital heart disease (75 percent), nervous sys-tem anomalies (77 percent) and Down syndrome(DS) (84 percent).86 The survival rate among maleswith congenital defects was 84 percent, comparedwith 97 percent in those born unaffected.24 Liuet al.87 examined temporal changes in fetal andinfant deaths caused by congenital malformationsin Canada, England, Wales, and the United States.They concluded that the major factor responsiblefor the accelerated decline in infant deaths was pre-natal diagnosis and elective abortion of fetuses withabnormalities. Given the frequency of DS, a moredetailed discussion follows.

Down syndromeThe special problems and associated defects in DSare well known, as is the increasing life expectancy.Studies from Japan,88 Denmark,89 England,90 Aus-tralia,91 and Canada92, 93 highlight the increasedlife expectancy with DS. Baird and Sadovnick92

reported a large study of 1,610 individuals with DSidentified in more than 1,500,000 consecutive live-births in British Columbia from 1908 to 1981. Theyconstructed survival curves and a life table for DS(Table 1.2) and for the general population.94 Theirestimates show that 44.4 percent and 13.6 percentof liveborn individuals with DS will survive to 60and 68 years, respectively, compared with 86.4 per-cent and 78.4 percent of the general population.In another report,95 these authors have analyzedthe causes of death in DS, highlighting congenitaldefects and cardiovascular and respiratory illnessesas the most important. A UK population prevalencestudy noted a median life expectancy of 58 years in2011.96

Additional studies of mortality rates in individu-als with DS revealed that those up to about 35 yearsof age were little different from others with intellec-tual disability. Thereafter, however, mortality ratesin DS doubled every 6.4 years, compared with 9.6

6 Genetic Disorders and the Fetus

Table 1.2 Life expectancy with Down syndrome, between

1908–1981, to age 68 years (excerpted from92)

Age Total

Survival at start of

age interval (%)

5 1,020 81.05

10 841 78.40

20 497 75.34

30 91 72.12

40 136 69.78

50 57 60.68

55 31 53.96

60 16 44.44

68 1 13.57

Source: Baird and Sadovnick 1989.94

years for other intellectually disabled individuals.95

Life tables constructed by these authors indicated alife expectancy of 55 years for a 1-year-old patientwith DS and mild/moderate developmental delayand a life expectancy of 43 years for a 1-year-oldpatient with DS more profoundly affected.

A study from the Centers for Disease Controland Prevention focused on the death certificates of17,897 individuals with DS born between 1983 and1997.97 These authors reported that the median ageat death for those with DS increased from 25 yearsin 1983 to 49 years in 1997 (Figure 1.1).

A 2009 Australian study found an overall sur-vival figure for DS of 90 percent to at least 5years of age.98 The known comorbidity of DS98–115

and earlier onset Alzheimer99 disease casts alonger shadow. In DS individuals over 40 yearsof age, increasing neuropsychological dysfunctionand loss of adaptive skills have been noted.115

Between 50–70 percent of DS patients developAlzheimer disease by 60 years of age,105 and upto 84 percent of those with dementia developseizures.102 A French study between 1979 and 1999found a sixfold decreased risk of death from uro-logical cancer in those with DS.112

Table 1.3 reflects the common associated defectsthat occur in DS,98–115 and the more commoncomplications that can be anticipated, moni-tored, prevented, and treated.116, 117 A EUROCATpopulation-based register study between 2000 and2010 in 12 countries analyzed 7,044 live birthsand fetal deaths with DS. This report116 notedthat 43.6 percent of births with DS had congenitalheart disease while 15 percent had another congen-

50 MenWomen

White peopleBlack peopleOther races

White without CHDWhite with CHDOthers without CHDOthers with CHD

40

30

20

Age

at d

eath

(ye

ars)

10

0

50

40

30

20

Age

at d

eath

(ye

ars)

10

0

50

40

30

20

Age

at d

eath

(ye

ars)

10

0

Year

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

Figure 1.1 Median age at death of people with Downsyndrome by sex (upper), by racial group (middle) and withor without congenital heart defects (CHD) by racial group(lower).Source: Yang et al. 2002.97 Reproduced with permission ofElsevier.

ital malformation. The National Society of GeneticCounselors published valuable guidelines for com-municating both prenatal and postnatal diagnosesof DS.104 A US population prevalence study esti-mated, in 2008, that there were 250,700 with DS.118

The goal and purpose of prenataldiagnosis

The fundamental philosophy of prenatal geneticdiagnosis is to provide reassurance to couples atrisk so that they may selectively have unaffectedchildren even if their procreative risk for havingoffspring with a genetic disorder is unacceptably

CHAPTER 1 Genetic Counseling: Preconception, Prenatal, and Perinatal 7

Table 1.3 Defects and complications associated with Down

syndrome

Defect or complication Prevalence (%)

Neurologic

Intellectual disability 100

Hypotonia 100

Alzheimer disease and dementia > 50

Obstructive sleep apnea 30–57

Behavior problems 18–38

Hearing impairment 12–78

Epilepsy 12–46

Psychiatric disorders 11–30

Heart

Mitral valve prolapse 57

Congenital heart disease ±50

Aortic valve regurgitation 17

Immune system

Susceptibility to infection 100

Hearing impairment 12–78

Juvenile rheumatoid-like arthritis 1.2

Gastrointestinal

Congenital defects of the

gastrointestinal tract

4–10

Celiac disease 2–20

Endocrine/metabolic

Obesity 30–35

Hypothyroidism 7–50

Diabetes mellitus 1.4–10.6

Hyperthyroidism 1–3

Ophthalmologic

Eye disordersa 80

Cataract 17–29

Keratoconus 8–10

Hematologic/oncologic

Leukemia > 20-fold excess

Testicular cancer Standardized

incidence ratio

of 4.8

Transient myeloproliferative

disorder

10

Retroperitoneal teratoma Increased

Musculoskeletal

Atlantoaxial instability 10–30

Osteoarthritis 8–28

Atlantoaxial subluxation 1–2

Dental

Orthodontic problems ±all

Periodontal disease ±all

Table 1.3 (Continued)

Defect or complication Prevalence (%)

Dermatologic

Dermatologic disorders 1.9–39.2

Urinary tract

Urinary tract anomalies 3.2

Notes: aIncludes strabismus, nystagmus, refractive errors,

glaucoma, and lens opacities.

Data from references.98,99–103,105–108

high.119 Fetal defects serious enough to warrantparental election of abortion are generally found inless than 5 percent of all cases studied, based oncurrent indications for prenatal diagnosis. Whencouples are at risk for having a child with a seri-ous or fatal disorder, common experience showsthat those with risks between 10 and 25 percent oreven greater most often avoid pregnancies unlessprenatal diagnosis is available. The advent of pre-natal diagnosis has made it possible for such high-risk couples to have children that they would oth-erwise never have conceived. As a consequence,the number of children born because of prenataldiagnosis is much higher than the very small num-ber of pregnancies terminated because of the detec-tion of grave fetal defects. Prenatal genetic studiesare used in Western society virtually exclusively forthe detection of defects generally characterized byirreparable intellectual disability and/or irremedia-ble serious to fatal genetic disease. Sadly, at present,the ideal goal of prevention or treatment, ratherthan abortion after prenatal detection of a fetaldefect, is achieved only rarely, with the exceptionof NTDs. Preimplantation genetic diagnosis (seeChapter 10) does, however, provide another optionthat avoids abortion.

All couples or individuals concerned about therisks of genetic disorders in their offspring shouldseek genetic counseling before conceiving. For themore common indications for prenatal diagnosis(such as a positive result on a noninvasive prena-tal screen – see Chapter 11 – or advanced maternalage), the well informed obstetrician should be ableto provide the necessary information.120, 121 How-ever, a salutary observation in one study revealedthat 43.3 percent of patients referred for amnio-centesis exclusively for advanced maternal age, hadadditional mostly unrecognized genetic risks, or

8 Genetic Disorders and the Fetus

significant concerns regarding one or more geneticor congenital disorders.122 Neither a questionnairein the physician’s office nor limited consultationtime is likely to reveal many of these disorders.

Prerequisites for geneticcounseling

Genetic counseling is a communication processconcerning the occurrence and the risk of recur-rence of genetic disorders within a family. Theaim of such counseling is to provide the counse-lee(s) with as complete an understanding of thedisorder and/or problem as possible and of all theoptions and implications. The counseling process isalso aimed at helping families cope with their prob-lems and at assisting and supporting them in theirdecision making.

The personal right to found a family is con-sidered inviolable. Such reproductive autonomy isenhanced by genetic counseling, a process thatboth emphasizes freedom of choice and reviews theavailable options in order to enrich the decision-making process. All couples have a right to knowwhether they have an increased risk of havingchildren with genetic disease and to know whichoptions pertain to their particular situation. Thephysician and genetic counselor have a clear dutyand obligation to communicate this information, tooffer specific tests or to refer couples for a second ormore expert opinion. In the United States, at least,the full force of law supports the prospective par-ents’ right to know.

As Kessler123 stated so succinctly, “Becausegenetic counselors work with people filled withuncertainty, fear of the future, anguish and a senseof personal failure” they have unusual challengesand opportunities “to understand clients, give thema sense of being understood and help them feelmore hopeful, more valued and more capable ofdealing with their life problems.” The physicianand genetic counselor providing genetic counsel-ing should have a clear perception of the neces-sary prerequisites, guiding principles and potentialproblems.

Knowledge of diseaseThe need for a counselor to have extensive fac-tual knowledge about disease in general, as well

as about the disease for which counseling is beingprovided, hardly needs emphasis. Such knowledgeshould include how the diagnosis is made andconfirmed, the test accuracy and limitations, theimportant comorbidities, the recurrence risks, themode of inheritance, the tests available to detect acarrier (and their detection rates), the heterogene-ity and pleiotropic nature of the disease, the qualityof life associated with survival, prognosis and thecauses of death. When relevant, it is necessary toknow about treatment and its efficacy.

The physician or genetic counselor who initiatesgenetic counseling for an apparently straightfor-ward indication (e.g. advanced maternal age) mayfind one or more other familial conditions withwhich he or she has little or no familiarity. Such cir-cumstances dictate referral for specialist consulta-tion. A National Confidential Enquiry into coun-seling for genetic disorders by nongeneticists inthe United Kingdom revealed that less than half ofthose with known high genetic risks were referredto medical geneticists.124 This study focused on areview of 12,093 “genetic events” involving poten-tially avoidable cases of DS, NTDs, cystic fibro-sis, β-thalassemia, and multiple endocrine neopla-sia. Medical record reviews were frustrated by thepoor quality of clinical notes, which lacked evi-dence of counseling. An urgent call was made forgenetic management to be at least as well docu-mented as surgical operations, drug records andinformed consent. A Dutch study evaluated the lev-els of knowledge, practical skills and clinical geneticpractices of 643 cardiologists. They noted low lev-els of self-reported knowledge and that only 38 per-cent had referred patients to clinical geneticists.125

Other physicians, too, have been found lackingin the necessary knowledge and communicationskills.126–129 Given the importance of genetic con-siderations in all specialties, these problems canbe anticipated to become more problematic, moreespecially in family practice.130

After the prenatal diagnosis of a serious geneticdisorder, the physician should be able to inform thefamily fully about the anticipated burden and todetail the effects of this burden on an affected child,the family, other siblings, the family economics andmarital relations, along with any other pros andcons of continuing pregnancy. The reality of earlyAlzheimer disease and other comorbidities in DS

CHAPTER 1 Genetic Counseling: Preconception, Prenatal, and Perinatal 9

and the care requirements that may devolve on thesiblings should not be omitted from the discussion.Exact details should also be known about the risksof elective abortion (see Chapter 29).

Expertise in genetic counselingGenetic counseling is best provided by board-certified clinical geneticists and genetic counselors.In countries with this specialization, such serviceis provided by a team composed of clinical geneti-cists (physicians) and genetic counselors, workingin concert with clinical cytogeneticists, biochemicaland molecular geneticists. It is, however, imprac-tical and not cost effective to provide such formalcounseling for every woman before prenatal diag-nosis for advanced maternal age. It is necessary forthe obstetrician to be fully informed about the indi-cations for amniocentesis and to explain the tech-niques and requirements for obtaining the tissue orfluid, the limitations of the studies, the risks of chro-mosomal abnormality in the offspring of the patientbeing counseled, the risks of the procedure and,when pertinent, all matters concerned with electiveabortion of an abnormal fetus.

Gordis et al.131 concluded that the way in whichan obstetrician managed patients at risk regardingreferral for genetic screening was closely related tothat obstetrician’s attitudes and education. Physi-cians in practice should be aware of the nuancesand needs in the genetic counseling process, includ-ing the key psychologic aspects.132 Perhaps mostimportant is the requirement that they recognizelimitations in their knowledge of uncommon orrare genetic disorders and be alert to situationsrequiring referral. Obstetricians or family prac-titioners are not expected to have an extensiveknowledge of all diseases but they should be able torecognize that a condition could be genetic. Con-cern about litigation should not act as a constantreminder to physicians of the need to consult orrefer.133–135

Ability to communicateMany physicians are not born communicators andmost have not had formal teaching and trainingto hone their communication skills. Recognizingthese deficiencies, the American Academy of Pedi-atrics has provided valuable guidance and madespecific recommendations for the development and

teaching of communication skills,136 as have oth-ers.137, 138

Simple language, an adequate allocation of time,and care and sensitivity are keys to successfulgenetic counseling. Technical jargon, used with dis-tressing frequency,139 is avoided only through con-scious effort. How an issue requiring a decision isframed,140 and the nature of the language used,141

may influence the patient’s choice.142 Counselingis facilitated when three key questions are asked:“Why did you come?” “What exactly do you hopeto learn?” and “Have I answered all your questionsand concerns?”

Although the explanation of exact statistical risksis important, patients often pay more attentionto the actual burden or severity of the disease inquestion. How risks are explained and expressedis a skill to be mastered. Key to the expositionis the patient’s educational level, cultural back-ground, and the requirement of an interpreter (whomay even bedevil a superb counselor). The use ofnumeric probabililties, relative risk, risk reductionor simple numbers of chance (1 in 100) or words(almost never, negligible, sometimes, more oftenthan not)143 are choices a counselor must make.Clearly, the simpler, the better and the more likelythe information is understood. Patients’ percep-tions of risk not infrequently differ markedly fromthose of the counselor, a realization that shouldelicit no comment. An essential ingredient of thecounseling process is time. The busy practitionercan hardly expect to offer genetic counseling duringa brief consultation. Distress and misunderstand-ing are invariable sequelae of such hastily deliveredcounseling.

Knowledge of ancillary needsFor the couple at high risk of having a child witha serious genetic disorder, prenatal diagnosis is notthe sole option. Even in situations in which a par-ticular disease is diagnosable prenatally, it is impor-tant to be certain that other avenues are explored.Prospective parents who are known, for example,to be carriers of an autosomal recessive disordermay be unaware of the possibility of sperm or ovumdonation, or may be unwilling to raise the question.This option may be viewed more favorably thanprenatal diagnosis and elective abortion. Physiciansshould be certain that their patients are familiar

10 Genetic Disorders and the Fetus

with all the aforementioned important options, aswell as with adoption, vasectomy, tubal ligation,treatments of the mother and/or fetus during preg-nancy, and other methods of assisted reproduc-tion (e.g. intracytoplasmic sperm injection,144 epi-didymal sperm aspiration,145 and preimplantationgenetic diagnosis) (see Chapters 5 and 10).

EmpathyEmpathy embodies the ability to not only under-stand the perspectives and emotions of others butto communicate that understanding.146 Much morethan the communication of risk figures for a partic-ular disorder is required in the genetic counselingprocess. Warmth, care, sympathy, understanding,and insight into the human condition are neces-sary for effective communication. The difficulty ofassimilating information and making rational deci-sions in the face of anxiety147 should be recognizedand vocalized. Empathy and sensitivity enable thecounselor to anticipate and respond to unspokenfears and questions, and are qualities that make thecounseling experience most beneficial and valuableto the counselees.

For example, a couple may have been trying toconceive for 10 years and, having finally succeeded,may be confronted by a callous physician who isimpatient about their concerns regarding amnio-centesis and elective abortion. Another couple mayhave lost their only child to a metabolic geneticdisease and may be seeking counseling to explorethe possibilities for prenatal diagnosis in a subse-quent pregnancy or even treatment following pre-natal diagnosis, as in the case of galactosemia. Theymay have in mind past problems encountered inprenatal diagnosis or may be aware of the uncertainoutcome of treatment. Or worse still, after a longhistory of infertility, pregnancy is achieved only tofind that the fetus has aneuploidy.

Sensitivity and awareness of the plight ofprospective parents are critical prerequisites andinclude the need to recognize and address the usu-ally unspoken fears and anxieties. They may havehad a previous affected child with physical/mentaldeficits and experienced stigmatizing encounters,including intrusive inquiries, staring and pointing,devaluing remarks and social withdrawal.148

Beyond the qualifications and factual knowl-edge of the counselor is the person, who is key to

successful and effective counseling. Attitude, bodylanguage, warmth, manners, dress, tone of voiceand personality are facets that seriously influencethe credibility and acceptance of the counselingoffered. Curiously, counselors rarely realize duringtheir counseling session that they are simultane-ously being assessed. Patients assess the apparentknowledge and credibility of the counselor, seekand are encouraged by evidence of experience, andconsider the information provided in light of thecounselor’s attitude, body language and other non-verbal characteristics. Staring at a computer screenwhile counseling conveys deep insensitivity.

Essential prerequisites for the empathetic geneticcounselor include the following:� Acknowledge the burden and empathize aboutthe sadness or loss (e.g. a previous child; recurrentmiscarriage; a deceased affected parent; a patientwho has experienced mastectomy and chemother-apy for breast cancer with daughters at risk).� Vocalize the realization of the psychologic painand distress the person or couple has experienced(e.g. recurrent pregnancy loss followed by multi-ple IVF efforts and subsequently a successful preg-nancy with a fetal defect).� Compliment the coping that has been necessary,including the stress a couple might have to endure,despite sometimes conflicting feelings.� Recognize (and explain) psychologic difficultiesin decision making when faced with a prenataldiagnosis of the same disorder affecting one parent(discussion of self-extinction, self-image and issuesof guilt and survival).� Fulfill the patient’s need for hope and support andactively avoid any thoughtless comments123 thatmay erode these fundamental prerequisites. Wellintentioned statements are frequently perceived ina very different way.136

It is self-evident that empathy would engendergreater patient satisfaction and may well be corre-lated with clinical competence.149

Sensitivity to parental guiltFeelings of guilt invariably invade the genetic con-sultation; they should be anticipated, recognized,and dealt with directly. Assurance frequently doesnot suffice; witness the implacable guilt of the obli-gate maternal carrier of a serious X-linked dis-ease.150 Explanations that we all carry harmful

CHAPTER 1 Genetic Counseling: Preconception, Prenatal, and Perinatal 11

genes often helps. Mostly, however, encouragementto move anguish into action is important. Thismight also help in assuaging any blame by the hus-band in such cases.151

Guilt is not only the preserve of the obligatecarrier. Affected parents inevitably also experienceguilt on transmitting their defective genes.152, 153

Frequently, parents express guilt about an occu-pation, medication or illegal drug that they feelhas caused or contributed to their child’s problem.Kessler et al.153 advised that assuaging a parent’sguilt may diminish their power of effective preven-tion, in that guilt may serve as a defense from beingpowerless.

Guilt is often felt by healthy siblings of an affectedchild, who feel relatively neglected by their par-ents and who also feel anger toward their par-ents and affected sibling. “Survivor guilt” is increas-ingly recognized, as the new DNA technologies areexploited. Experience with Huntington disease andadult polycystic kidney disease154–160 confirm notonly survivor guilt with a new reality (a future)but also problems in relationships with close familymembers. Huggins et al.157 found that about 10 per-cent of individuals receiving low-risk results expe-rienced psychologic difficulties.

Guiding principles for geneticcounseling

Eleven key principles are discussed that guidegenetic counseling in the preconception, prenataland perinatal periods. This section is in concertwith consensus statements concerning ethical prin-ciples for genetics professionals161–163 and surveyedinternational guidelines.164

Accurate diagnosisClinical geneticists, obstetricians or pediatriciansare frequently the specialists most confrontedby patients seeking guidance because of certaingenetic diseases in their families. A previous childor a deceased sibling or parent may have had thedisease in question. The genetic counseling pro-cess depends on an accurate diagnosis. Informa-tion about the exact previous diagnosis is impor-tant not only for the communication of subsequentrisks but also for precise future prenatal diagnosis.Now whole exome or genome sequencing and the

demonstrated potential diagnostic yield of 25–42percent for previously undiagnosed patients withsevere intellectual disability10, 165, 166 introduce clin-ical demands to be up to date and well informed.It is not sufficient to know that the previous childhad a mucopolysaccharidosis; exactly which typeand even subtype must be determined because eachmay have different enzymatic deficiencies or geno-types (see Chapter 22). A history of limb-girdlemuscular dystrophy will also not facilitate prena-tal diagnosis because there are eight dominant types(1A–1H), at least 23 autosomal recessive types (2A–2W),167 and many are still to be molecularly iden-tified. Similarly, a history of epilepsy gives no clearindication of which genes are involved.168 Birth ofa previous child with craniosynostosis requires pre-cise determination of the cause (where possible)before risk counseling is provided. Mutations in atleast 13 genes are clearly associated with mono-genic syndromic forms of craniosynostosis.169–171

Moreover, a chromosomal abnormality may be thecause.

Awareness of genetic heterogeneity and ofintrafamily and interfamily phenotypic variationof a specific disorder (e.g. tuberous sclerosis)172

is also necessary. The assumption of a particularpredominant genotype as an explanation for afamilial disorder is unwarranted. The commonadult-dominant polycystic kidney disease dueto mutations in the ADPKD1 gene has an earlyinfancy presentation in 2–5 percent of cases.173

Moreover, mutations in the ADPKD2 gene mayresult in polycystic kidney disease and perinataldeath174 and, further, should not be confused withthe autosomal recessive type due to mutationsin the ARPKD gene. Awareness of contiguousgene syndromes, such as tuberous sclerosis andpolycystic kidney disease (TSC2-PKD1) hasbecome increasingly important, especially with theavailability of microarrays.

Instead of simply accepting the patient’s nam-ing of the disease (e.g. muscular dystrophy or amucopolysaccharidosis), or that a test result wasnormal (or not), the counselor must obtain anddocument confirmatory data. The unreliability ofthe maternal history, in this context, is remark-able, a positive predictive value of 47 percent havingbeen documented.175 Photographs of the deceased,autopsy reports, hospital records, results of carrier

12 Genetic Disorders and the Fetus

detection or other tests performed elsewhere, andother information may provide the crucial confir-mation or negation of the diagnosis made previ-ously. Important data after miscarriage may alsoinfluence counseling. In a study of 91 consecutive,spontaneously aborted fetuses, almost one-thirdhad malformations, most associated with increasedrisks in subsequent pregnancies.176

Myotonic muscular dystrophy type 1 (DM), themost common adult muscular dystrophy, with anincidence of about 1 in 8,000,177 serves as theparadigm for preconception, prenatal and perinatalgenetic counseling. Recognition of the pleiomor-phism of this disorder will, for example, alert thephysician hearing a family history of one individ-ual with DM, another with sudden death (cardiacconduction defect), and yet another relative withcataracts. Awareness of the autosomal dominantnature of this disorder and its genetic basis due toa dynamic mutation reflected in the number of tri-nucleotide (CTG) repeat units, raises issues beyondthe 50 percent risk of recurrence in the offspringof an affected parent. As the first disorder char-acterized with expanding trinucleotide repeats, theobservation linking the degree of disease severityto the number of triplet repeats was not long incoming.177 In addition, the differences in sever-ity when the mutation was passed via a maternalrather than a paternal gene focused attention onthe fact that congenital DM was almost always asign of the greatest severity and originating throughmaternal transmission. However, at least one excep-tion has been noted.178 There is about a 93–94 per-cent likelihood that the CTG repeat will expandon transmission. This process of genetic anticipa-tion (increasing clinical severity over generations)is not inevitable. An estimated 6–7 percent of casesof DM are associated with a decrease in the numberof triplet repeats or no change in number.179 Rarecases also exist in which complete reversal of themutation occurs with spontaneous correction to anormal range of triplet repeats.180–183

There are also reports of patients born with adecreased number of triplet repeats who never-theless show no decrease in the severity of theirDM.184–186 It is unclear whether these cases in partreflect somatic or germline (either or both com-bined) mosaicism.179 Somatic mosaicism is cer-tainly well documented in DM with, for exam-

ple, larger expansions being observed in skele-tal muscle than in peripheral blood.187 Discus-sion about potential complications of pregnancyin the prospective affected mother is crucial,188

and includes pregnancy loss, polyhydramnios, pro-longed labor, uterine atony, postpartum hemor-rhage, cardiac arrhythmias, increased sensitivityto anesthetic and relaxant agents, newborn apnea,neonatal death, arthrogryposis and intellectualdisability.

Myotonic muscular dystrophy type 2 (DM 2), incontrast to DM 1, has more prominent proximalmuscle weakness compared with distal weakness ofDM 1. While multisystem involvement is similar inboth types, neither congenital myotonic musculardystrophy nor anticipation occurs in DM 2.189 Car-diac involvement in DM 2 also is less frequent andless severe than DM 1.190 DM 2 results from a largetetranucleotide repeat (CCTG) within an intron inCNBP gene. Again in contrast to DM 1, the DM 2repeat number may contract rather than increaseover generations.189

The lack of CAG triplet expansion among indi-viduals presenting with Huntington disease-likesymptoms and a family history of neurodegenera-tive disease has focused attention on phenocopiesof Huntington disease.191 Estimates of such pheno-copies range between 1 and 2.4 percent of patientsmanifesting Huntington disease-like signs with afamily history of a neurodegenerative disorder.192

Among the reported phenocopies found thus farare a familial prion disease191 and a triplet expan-sion (CAG/CTG) in the junctophilin-3 gene onchromosome 16 in patients presenting with Hunt-ington disease-like manifestations.193

The recognition in 2011 of a hexanucleotiderepeat expansion in C9ORF72 as the cause ofeither or both amyotrophic lateral sclerosis (ALS)and frontotemporal dementia194, 195 revealed aneurological spectrum clearly recognized previ-ously.196 Between 40–50 percent of those affectedby familial ALS have the characteristic expan-sion. About 15 percent of patients with ALS alsohave frontotemporal dementia, while 50 percenthave some cognitive and/or behavioral dysfunc-tion.196 Of those patients who present with fron-totemporal lobe degeneration, the extreme end ofthe spectrum, 15 percent also have ALS. Hence,assessment of the family history in an effort to