Genetic Disorders and the Fetus. Группа авторов

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 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.¹² In 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

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