Genetic Disorders and the Fetus

Florida International University

Miami, FL, USA

President

Reproductive Genetic Innovations

Northbrook, IL, USA

Wendy P. Robinson, phd

Professor, Department of Medical Genetics

University of British Columbia

Senior Scientist

Child and Family Research Institute

Vancouver, BC, Canada

David S. Rosenblatt, mdcm, fccmg, frcpsc, faap, facmg

Dodd Q. Chu and Family Chair in Medical Genetics

Professor

Departments of Human Genetics

Medicine, Pediatrics, and Biology

Faculties of Medicine and Science

McGill University

Montreal, Quebec, Canada

Michael G. Ross, md, mph

Distinguished Professor of Obstetrics and Gynecology and Public Health

Geffen School of Medicine at University of California Los Angeles

Fielding School of Public Health at UCLA

Los Angeles, CA, USA

Co‐Director Institute for Women' and Children's Health

The Lundquist Institute at Harbor‐UCLA Medical Center

Torrance, CA, USA

Marisa E. Schwab, md

Surgery Resident

The Center for Maternal‐Fetal Precision Medicine and Department of Surgery

University of California, San Francisco

San Francisco, CA, USA

Alireza A. Shamshirsaz

Associate Professor of Surgery, Obstetrics and Gynecology

Departments of Obstetrics and Gynecology and Surgery

Baylor College of Medicine

Chief, Division of Fetal Therapy and Surgery

Co-Chief, Maternal Fetal Surgery Section

Texas Children's Fetal Center

Texas Children's Hospital

Houston, TX, USA

Lee P. Shulman, md, facmg, facog

The Anna Ross Lapham Professor in Obstetrics and Gynecology

Feinberg School of Medicine of Northwestern University

Medical Director, Insight Medical Genetics

Medical Director, Reproductive Genetic Innovations

Chicago, IL, USA

Andrea Superti‐Furga, md

Professor of Pediatrics

University of Lausanne

Head, Division of Genetic Medicine

Lausanne University Hospital

Lausanne, Switzerland

Jan Traeger‐Synodinos, dphil (Oxon), erclg

Professor of Genetics

Director of the Laboratory of Medical Genetics

National and Kapodistrian University of Athens, Greece

Sheila Unger, md, frcpc

Chief

MER1 Division of Genetic Medicine

Lausanne University Hospital

Lausanne, Switzerland

Ignatia B. Van den Veyver, md

Professor of Obstetrics and Gynecology and Molecular and Human Genetics

Baylor College of Medicine;

Director of Clinical Prenatal Genetics

Texas Children's Hospital

Houston, TX, USA

Daniel L. Van Dyke, phd

Professor of Laboratory Medicine and Pathology

Mayo Medical School and Mayo Clinic Cytogenetics Laboratory

Rochester, MN, USA

Liesbeth van Leeuwen, md, phd

Associate Professor

Department of Obstetrics

Amsterdam Reproduction and Development Research Institute

Amsterdam University Medical Centers

University of Amsterdam

Amsterdam, The Netherlands

Yves G. Ville, md

Professor of Obstetrics and Fetal Medicine

Head of Department of Obstetrics and Fetal Medicine

Hôpital Necker‐Enfants Malades, GH Paris‐Centre

Université de Paris

Paris, France

Gerard Vockley, md, phd

Professor of Pediatrics and Human Genetics

Cleveland Family Endowed Professor of Pediatric Research

Department of Pediatrics

University of Pittsburgh School of Medicine and Graduate School of Public Health

Chief, Division of Medical Genetics

Director, Center for Rare Disease Therapy

Children's Hospital of Pittsburgh

Pittsburgh, PA, USA

Ronald J.A. Wanders

University of Amsterdam, Academic Medical Center

Departments of Clinical Chemistry and Pediatrics

Emma Children's Hospital

Laboratory of Genetic Metabolic Diseases

Amsterdam, The Netherlands

Hans R. Waterham, phd

Professor, Functional Genetics of Metabolic Diseases

Departments of Laboratory Medicine and Pediatrics

University of Amsterdam

Academic Medical Center

Laboratory for Genetic Metabolic Diseases

Amsterdam, The Netherlands

David Watkins, phd

Research Associate

Department of Human Genetics

McGill University

Scientist

Division of Medical Genetics, Department of Specialized Medicine

McGill University Health Centre

Montreal, Quebec, Canada

Bryan G. Winchester, ma, phd

Emeritus Professor of Biochemistry

ULC Great Ormond Street Institute of Child Health

University College London

London, UK

Aline Wolter, md

Justus‐Liebig‐University, Giessen

Department of Obstetrics and Gynecology

Division of Prenatal Medicine and Fetal Therapy

University Hospital

Giessen, Germany

Ellen Wright Clayton, md, jd

Craig‐Weaver Professor of Pediatrics

Professor of Law

Center for Biomedical Ethics and Society

Vanderbilt University

Nashville, TN, USA

Aubrey Milunsky 1,2 and Jeff M. Milunsky 1,2

1Center for Human Genetics, Cambridge, MA, USA

2Tufts University School of Medicine, Boston, MA, USA

The time is fast approaching when virtually all the culprit genes and their mutations for >7,000 rare monogenic disorders 1will be known. Thus far, causal single genes and their mutations have been determined for 5,673 genetic disorders, 2enabling preimplantation genetic testing or prenatal genetic diagnosis. These advances using chromosomal microarrays, whole‐exome sequencing and even whole‐genome sequencing together with fetal imaging and noninvasive prenatal testing, expand the era in which all couples have the option of avoiding or preventing having children with irreversible, irremediable, crippling, or lethal monogenic disorders. Primary care physicians, and those in all medical specialties, will need to inform their patients of this key option. This imperative is already partly in current practice. Missing is the requirement of physicians to request and obtain the precise name of the genetic disorder in question or an existing DNA report on a family member, for prospective parents to benefit from available options.

Increasingly, couples are seeking prenatal diagnosis for adult‐onset genetic disorders in which mutations have been determined. Huntington disease prenatal diagnosis has been in the vanguard for many years, but now there are requests for adult‐onset dominantly transmissible disorders including breast and other malignancies, frontotemporal dementia, neurodegenerative disorders, and cardiomyopathies. The remarkable advances in genetics provide a cogent need to confer and refer. Physicians should not invite legal purview for a failure to inform, offer, refer, or provide genetic testing.

In context, couples at risk for having progeny with abnormalities expect to be informed about their risks and options, optimally during preconception counseling. Their concerns are serious, given the significant contribution of genetic disorders to morbidity and mortality in children and adults.

A conservative estimate for the world population prevalence of rare diseases (71.9–80 percent considered as genetic) is 3.5–5.9 percent, equating to 263–446 million individuals affected at any point in time. 3 , 4In India, which has a quarter of the world's neonatal deaths (an estimated 753,000 in 2013), about 9 percent were due to congenital anomalies. 5An estimated 7.9 million infants worldwide are born each year with a major congenital malformation according to a report in 2013. 6The likelihood of having a child with a congenital malformation varies from 2 to 10 percent 7due to multiple factors that complicate efforts to accurately diagnose and determine the incidence or prevalence of congenital anomalies or genetic disorders. Box 1.1lists the majority of known etiologic categories, discussed below, which help explain sometimes striking differences among major studies. It is almost impossible to account for all these potentially confounding factors in a study, and rarely has any one study come close. Of the >7,000 rare genetic disorders, about 1 in 12 to 1 in 16 individuals are affected, 1aware or unaware. Given a world population of 7.6 billion, an estimated 473 million are likely to have a rare disease. 1More than 4,331 genes with phenotype‐causing mutations have been identified, including 6,739 phenotypes with a known molecular basis. 2Severe intellectual disability is considered to be largely genetic in origin 8 , 9with a global prevalence between 0.5 and 1.0 percent. 10Despite continuing progress in the discovery of genes causally related to neurodevelopmental delay, 11in less than 40 percent of cases is there a definitive recognition of cause. The European Organization for Rare Diseases maintained that about 30 percent of all patients with a rare disease died before the age of 5 years. 12In the United States in 2013–2014, congenital malformations, deformations, and chromosomal abnormalities accounted for the most infant deaths – 4,746 (20.4 percent) out of 23,215 – in any category of causation. 13