Genetic Disorders and the Fetus. Группа авторов

       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

1 Genetic Counseling: Preconception, Prenatal, and Perinatal

      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 disorders¹ will be known. Thus far, causal single genes and their mutations have been determined for 5,673 genetic disorders,² enabling 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.

The burden of genetic disorders and congenital malformations

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, 4} In 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.⁵ An estimated 7.9 million infants worldwide are born each year with a major congenital malformation according to a report in 2013.⁶ The likelihood of having a child with a congenital malformation varies from 2 to 10 percent⁷ due to multiple factors that complicate efforts to accurately diagnose and determine the incidence or prevalence of congenital anomalies or genetic disorders. Box 1.1 lists 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,¹ aware or unaware. Given a world population of 7.6 billion, an estimated 473 million are likely to have a rare disease.¹ More than 4,331 genes with phenotype‐causing mutations have been identified, including 6,739 phenotypes with a known molecular basis.² Severe intellectual disability is considered to be largely genetic in origin^{8, 9} with a global prevalence between 0.5 and 1.0 percent.¹⁰ Despite continuing progress in the discovery of genes causally related to neurodevelopmental delay,¹¹ in less than 40 percent