Shortcomings of ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish ancestry

Purpose: Carrier screening identifies reproductive risk for autosomal recessive and X-linked genetic conditions. Currently, some medical society guidelines continue to recommend ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish (AJ) ancestry. We assessed the utility and limitations of these guidelines in a large, ethnically and genetically diverse cohort of genotyped individuals. Methods: We characterized the self-reported ethnicity and genetic ancestry of over 110,000 consenting research participants identified as heterozygous for pathogenic variants associated with 15 autosomal recessive conditions recommended by the American College of Obstetricians and Gynecologists for screening in individuals of AJ descent. Results: Out of 7.2 million research participants, 116,517 research participants were identified as heterozygous for pathogenic variants associated with 15 conditions evaluated. The majority (54.9%) of heterozygotes did not report qualifying ethnicity under American College of Obstetricians and Gynecologists ethnicity-based screening guidelines. Approximately half (51.3%) of all individuals heterozygous for pathogenic variants in genes associated with 1 or more conditions recommended to be screened exclusively in individuals of AJ descent had <20% computed AJ ancestry. Conclusion: Ethnicity-based carrier screening leads to the under detection of heterozygotes and associated reproductive risk for conditions historically associated with AJ ancestry.