© 2019 Myriad Genetics. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. 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.