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Counsyl Study Finds Expanded Carrier Screening More Effective Than Standard Testing

NEW YORK (GenomeWeb) – Counsyl researchers have found that expanded carrier screening would likely identify individuals who carry disease-associated alleles and would not have been screened if following standard recommendations.

The work, published today in the Journal of the American Medical Association, adds to a growing body of evidence suggesting that traditional carrier screening, based on guidelines set by the American College of Obstetrics and Gynecologists and the American College of Medical Genetics and Genomics, may miss many individuals who do in fact carry risk alleles for severe diseases. The study also highlights gaps in our knowledge population-based carrier frequency.

The study, conducted and funded by genetic testing firm Counsyl, included nearly 350,000 adults from diverse ethnic backgrounds who had been tested between 2012 and 2015 with Counsyl's Family Prep Screen, which analyzes carrier status in up to 110 genes involved in 94 autosomal or X-linked recessive, severe conditions.

The test requisition forms required individuals to choose one of 15 ethnic backgrounds, defined on the basis of professional guidelines like Ashkenazi Jewish, known genetic founder populations like Finnish, and US census guidelines. Mixed-race and unknown options were also included.

Physicians could select from one of two versions of the Family Prep Screen test, a genotyping version that assessed 417 variants, or a next-generation sequencing version that targeted variants in selected exons and introns of up to 110 genes. And, they could also customize the tests, choosing to analyze all 110 genes, or just a subset.

The researchers analyzed the results of those tests and then calculated the risk of having a fetus with one of the disorders based on random hypothetical pairings and the fetus' ethnicity. The researchers primarily focused on analyzing hypothetical couples of the same ethnic backgrounds. They compared that risk to an estimated risk using ACMG and ACOG guidelines, which are based on current knowledge of allele frequencies in various populations. ACOG and ACMG recommend carrier testing for different diseases depending on an individual's ethnicity.

Overall, expanded carrier screening identified more hypothetical fetuses with a disorder, both because the tests assessed more variants than would have been assessed by recommended guidelines based on individuals' reported ethnicities, and also because guideline-based testing relies in part on "self-identified racial/ethnic categories," the authors noted.

For instance, among the Ashkenazi Jewish population, 55 percent of hypothetically affected fetuses would not have been identified had individuals received guideline-based testing, the authors reported. Among Middle Eastern couples, 91 percent of affected fetuses would not have been identified using a guideline-based panel, the researchers found.

In addition, there was a wide discrepancy in detection rates for guideline-based panels among the different ethnicities, with more affected fetuses identified in well-studied populations. Expanded carrier screening, meantime, which was done irrespective of self-reported ethnicity, helped to narrow that discrepancy.

The study is not the first to suggest that expanded pan-ethnic carrier screening could be better at detecting at risk couples than the current standard testing. Good Start Genetics presented data at a conference last year from its pan-ethnic carrier screening test, GoodStart Select, which assesses carrier status for 23 disorders, showing that between 16 percent and 22 percent of carriers would have been missed with traditional screening methods. 

Professional societies have also acknowledged the potential benefit of expanded carrier screening, and last year, the ACMG, ACOG, the Maternal Society for Maternal-Fetal Medicine, the National Society for Genetic Counselors, and the Perinatal Quality Foundation issued a joint statement on expanded carrier screening. The statement did not endorse the use of such tests nor provide specific guidelines on who should use them and in what circumstances, but rather sought to lay out the benefits and risks of such testing.

Wayne Grody, professor at the University of California, Los Angeles' Division of Molecular Diagnostics and Clinical Genomics Center, wrote in an accompanying editorial, also published today in JAMA, that the recent Counsyl study is an "important contribution in the evolving field of prenatal testing" that "provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds." However, "there needs to be convincing evidence before they all are tested for and possibly acted upon," he wrote. "Especially in the emotionally charged prenatal setting, a cautious approach to prenatal carrier screening along with a great deal of additional thought in designing such programs is the most prudent course of action," he added.