Expanded, Panethnic Carrier Screening May Be More Effective

Expanded carrier screening may significantly increase the detection of carrier status for severe genetic conditions, compared to current screening guidelines, according to a study published in the Aug. 16 issue of the Journal of the American Medical Association. Additionally, universal expanded carrier screening can help narrow the discrepancy in detection rates among different ethnicities, the authors say.

“Expanded carrier screening revealed that many non-European racial/ethnic categories have a risk of profound or severe genetic disease that may not be detected by the guidelines in place at this time of analysis,” write the authors led by Imran Haque, Ph.D., vice president of scientific affairs at molecular testing firm Counsyl (South San Francisco, Calif.).

Currently, carrier status is screened for a limited number of single-gene conditions, partially based on the patient’s ethnicity. Experts say that for a disorder to be included in recommended population-based carrier screening guidelines the condition must be relatively frequent, associated with well-characterized, predictive mutations, and uniformly severe clinically. Even still, there is a lack of consistency in national organizations’ recommendations—the American Congress of Obstetricians and Gynecologists (ACOG) only recommends universal screening for cystic fibrosis, while the American College of Medical Genetics and Genomics (ACMG) recommends both cystic fibrosis and spinal muscular atrophy testing for all.

Counsyl conducted retrospective modeling analysis of results from expanded carrier screening conducted on 346,790 reproductive-aged individuals (Jan. 1, 2012 to July 15, 2015) without a known indication for genetic testing. Testing used Counsyl’s Family Prep Screen on either a targeted genotyping or next-generation sequencing platform. The test screens for status of 110 genes causing 94 autosomal or X-linked recessive conditions, including rare and ultra-rare disorders. The laboratory reported only known and likely pathogenic variants. Results were based on 11 self-reported racial/ethnic categories with a minimum of 5,000 samples.

The researchers found that the frequency of fetuses potentially affected by a profound or severe condition ranged from 94.5 per 100,000 for Hispanic couples to 392.2 per 100,000 for Ashkenazi Jewish couples. In all racial/ethnic categories, except African or African American and Southeast Asian, the expanded carrier panel would detect at least twice as many hypothetical fetuses with severe and profound diseases versus testing using the ACOG and ACMG panel recommendations.

“Just because these variants can now be detected, there needs to be convincing evidence before they all are tested for and possibly acted upon,” cautions Wayne Grody, M.D., Ph.D., from University of California, Los Angeles, in an accompanying editorial. “Every additional disease screened requires additional genetic counseling resources to convey the results and risks of the test. … In the emotionally charged prenatal setting, a cautious approach to prenatal carrier screening … is the most prudent course of action.”

Takeaway: Despite the optimism that expanded, panethnic carrier screening can identify more potential risk of severe and profound diseases, there needs to be some caution in how to practically counsel clients on a potentially large number of variants.