Pathogenic variants in the BRCA1 and BRCA2 (BRCA1/2) genes are associated with elevated cancer risks in men and women. Due to a founder effect, Ashkenazi Jewish individuals are at higher risk for carrying three specific BRCA1/2 pathogenic variants. There have been recent calls for population screening in this population because many carriers do not have family histories suggestive of hereditary cancer. One approach could be to integrate optional BRCA1/2 testing into routinely offered reproductive carrier screening for recessive and X-linked disorders. However, the differing goals of these types of testing (i.e., personal health risks versus family planning) raise questions about the implications for patient education and informed consent. To this end, we aimed to determine interest, attitudes, and preferences regarding integrating such testing by electronically surveying 331 Ashkenazi Jewish participants in JScreen — a national, not-for-profit, at-home carrier screening program focused on genetic risks in Jewish communities. We found that while 41% of participants had plans to pursue BRCA1/2 testing, 93% would have opted for such testing if offered as an add-on to reproductive carrier screening. This was particularly true of those with higher perceived cancer risk and more positive attitudes toward genetic testing. With respect to preferences about delivery of this service, more than 85% of participants preferred remote (telephone, print, or web-based) genetic education rather than traditional genetic counseling. These results suggest that offering optional BRCA1/2 testing within the context of reproductive carrier screening might provide opportunities for cancer prevention without overburdening scarce genetic counseling resources.

Background: Pathogenic variants in HEXA that impair β-hexosaminidase A (Hex A) enzyme activity cause Tay-Sachs Disease (TSD), a severe autosomal-recessive neurodegenerative disorder. Hex A enzyme analysis demonstrates near-zero activity in patients affected with TSD and can also identify carriers, whose single functional copy of HEXA results in reduced enzyme activity relative to noncarriers. Although enzyme testing has been optimized and widely used for carrier screening in Ashkenazi Jewish (AJ) individuals, it has unproven sensitivity and specificity in a pan-ethnic population. The ability to detect HEXA variants via DNA analysis has evolved from limited targeting of a few ethnicity-specific variants to next-generation sequencing (NGS) of the entire coding region coupled with interpretation of any discovered novel variants. Methods: We combined results of enzyme testing, retrospective computational analysis, and variant reclassification to estimate the respective clinical performance of TSD screening via enzyme analysis and NGS. We maximized NGS accuracy by reclassifying variants of uncertain significance and compared to the maximum performance of enzyme analysis estimated by calculating ethnicity-specific frequencies of variants known to yield false-positive or false-negative enzyme results (e.g., pseudodeficiency and B1 alleles). Results: In both AJ and non-AJ populations, the estimated clinical sensitivity, specificity, and positive predictive value were higher by NGS than by enzyme testing. The differences were significant for all comparisons except for AJ clinical sensitivity, where NGS exceeded enzyme testing, but not significantly. Conclusions: Our results suggest that performance of an NGS-based TSD carrier screen that interrogates the entire coding region and employs novel variant interpretation exceeds that of Hex A enzyme testing, warranting a reconsideration of existing guidelines.