In the fast-moving field of molecular diagnostics, the American College of Medical Genetics and Genomics (ACMG) recently released guidance on two emerging issues of importance: non-invasive prenatal screening for fetal aneuploidy (NIPS) and reporting incidental findings from whole exome or genome sequencing.

In a policy statement on NIPS, ACMG noted that analyzing cell-free fetal DNA from maternal blood for fetal aneuploidy is likely the first of major steps toward fetal genome or exome sequencing. Promising studies of this method have shown high sensitivity and specificity with a low false-positive rate. However, ACMG cited 10 limitations of NIPS, including: identifying only three aneuploidies—leaving undetected about half those picked up by amniocentesis; not detecting chromosomal abnormalities such as deletions and duplications; and having longer turnaround times than tests of maternal serum analytes. For these reasons, ACMG recommends that women undergo invasive testing to confirm positive NIPS results.

Pre- and Post-Test Counseling Crucial

The statement called on laboratory reports to state clearly that NIPS is a screening, not diagnostic, test, and to clarify the need for post-test counseling for patients with screen-positive or screen-uninformative results.

ACMG also issued recommendations for reporting incidental findings from whole exome or genome sequencing. This document, which followed a policy statement on clinical sequencing and was a year in the making, was crafted by a special working group. The panel noted that the rapid advance of exome and genome sequencing has made it possible to use these methods in a variety of clinical settings, all of which have the potential to expose incidental findings that were not the reason for the sequencing. Considerable literature has explored both the utility and ethics of incidental findings in research settings, but little exists in the clinical realm, and is particularly lacking to support evidence-based recommendations. Even so, the working group arrived at consensus based on available evidence.

The panel compiled a list of 24 conditions and associated genes and variants that should be reported for incidental findings in all patients regardless of age, ranging from hereditary breast and ovarian cancer (BRCA1/2) and familial hypercholesterolemia, to Lynch syndrome and hypertrophic or dilated cardiomyopathy. The working group prioritized this list for conditions in which treatments or preventive measures exist and for which confirmatory diagnostic approaches are available.

The panel recommended against patient choice about receiving the findings, noting that “clinicians and laboratory personnel have a fiduciary duty to prevent harm by warning patients and their families about certain incidental findings and that this principle supersedes concerns about autonomy.” However, the authors also emphasized that incidental findings should be reported only to the ordering clinician, who could put them in the context of the patient’s personal and family medical history, physical examination, and other factors. Laboratory reports of incidental findings should specify with “distinct language” how the quality of those findings differs from the quality of molecular testing for the primary investigation.

Finally, the working group cautioned that its recommendations reflect current technology, and that the list of recommended conditions should be updated annually.

The documents are available online.