Genomics and Perinatal Care — NEJM

full-text:
Genomics and Perinatal Care — NEJM

W. Gregory Feero, M.D., Ph.D., Editor, Alan E. Guttmacher, M.D., Editor

Genomics and Perinatal Care

Joann Bodurtha, M.D., M.P.H., and Jerome F. Strauss, III, M.D., Ph.D.

N Engl J Med 2012; 366:64-73January 5, 2012

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Genomics and Perinatal Care: Methods of Preimplantation Genetic Diagnostics.

Among both prospective parents and providers of medical care, genetic and social concerns peak during the perinatal period. Advances in genomics and assisted reproductive technology have created new opportunities to detect genetic disorders and susceptibilities at multiple times during perinatal care and thus are relevant to these concerns. Emerging therapies for single-gene disorders may reshape these discussions.

Practitioners working with persons wishing to be parents are encouraged to inquire about their genetic backgrounds and family histories, to counsel them about tests for disease-carrier status that are based on known population-specific risks,1 and to refer them, when appropriate, to specialists in high-risk pregnancy and genetics. Nonetheless, there are major differences across the world in the adoption and implementation of genetic education and screening practices by providers, women and their partners, and health payment systems.2,3 Such differences are to be expected because access to health care, along with the availability of genetic counseling and testing, varies.

Even in the best-case scenario, patients, practitioners, and policymakers face complicated choices when selecting which genomic techniques to use broadly or individually in assessing risk and in determining how laboratory findings should inform decision making as the options for genetic testing expand.4 For example, it is not always possible to predict a priori the severity of a clinical condition on the basis of a genotype. A laboratory result may be flawless, but the identified genetic variation may not be known to cause a disease (i.e., it is a variant of uncertain significance). Or the discovered mutation or variant in a known disease gene may not reliably correlate with phenotype because of the influence of modifiers, which can be genetic, epigenetic, or environmental.

Preconception Genetic Screening and Testing

Genetic risk, especially of known genetic conditions in the family or a previous pregnancy, should ideally be assessed before conception or the establishment of a pregnancy in the context of assisted reproductive technology. Genetic screening is offered for a particular condition (or group of conditions) in individuals, groups, or populations. A family history of the condition is not required for genetic screening. Genetic testing is generally carried out when there is suspicion that an individual is at increased risk because of family history or because of a positive result on a biochemical screening test.

The American Congress of Obstetricians and Gynecologists (ACOG) recommends that women be offered information about genetic risk, including the risk of carrying mutant alleles that cause cystic fibrosis, hemoglobinopathies, and diseases typically affecting those of Eastern European Jewish ancestry.1,5-10 The American College of Medical Genetics (ACMG) recommends a more extended screening panel for those of Eastern European Jewish ancestry and the offering of carrier testing for spinal muscular atrophy to all couples, regardless of race or ethnic background.11-16 Identifying carriers of autosomal recessive or X-linked conditions before conception allows more informed decisions about reproductive options.

Different methods are used for screening, depending on whether chromosomes, proteins, related products of a gene (e.g., RNA), or nuclear or mitochondrial DNA are examined. Contemporary carrier screening involves tests for the most common mutations and for specific diseases in specific populations. Recent advances in DNA sequencing and bioinformatics have led to an approach for identifying carriers of known mutations that cause more than 400 recessive genetic diseases.17 However, this approach may miss some mutations and thus not identify some carriers.

In the case of carrier screening for Tay–Sachs disease (hexosaminidase deficiency, which is most prevalent in persons of Eastern European Jewish ancestry), the hexosaminidase enzyme assay remains the primary method of screening because it has greater sensitivity than targeted DNA mutation analysis. (Screening for the three most common hexosaminidase gene mutations detects 92 to 94% of carriers.18) However, there are now genetic tests that use the less sensitive targeted-mutation strategy for Tay–Sachs disease and that simultaneously test for the presence of mutations causing other genetic conditions for which this population is at increased risk, thus trading higher sensitivity for Tay–Sachs carrier status for a broader range of disease detection. Consequently, clinicians who are recommending such screening should have knowledge of current professional society guidelines, provide informed consent about the sensitivity and specificity of tests, and be able to make an appropriate referral for complex results