Value Of The Continued Use Of The Hexosaminidase A Enzyme Assay For Reproductive Carrier Screening

INTRODUCTION: With the trend towards next-generation screening (NGS) for reproductive carrier screening, the value of Hexosaminidase A (HexA) enzyme assays for detecting Tay-Sachs Disease (TSD) and Sandhoff Disease (SD) carriers has been debated. METHODS: Results were analyzed for 27,121 individuals of varied self-reported ethnicities who underwent clinical Hex A enzyme testing as well as HEXA/HEXB NGS. RESULTS: 481 TSD enzyme carriers were identified, of which 55% could be attributed to HEXA pathogenic (P)/likely pathogenic (LP)/pseudodeficiency (PD) variants, with Ashkenazi Jews and African Americans giving the highest and lowest collective yields, respectively. Of 186 identified SD enzyme carriers, 39% could be attributed to HEXB P/LP/PD variants, with Asians and Ashkenazi Jews giving the highest and lowest yields, respectively. The rate of HEXA variants of uncertain significance (VUSes) in TSD enzyme carriers was 11%, which is 5.4X higher than the rate in individuals with normal enzyme levels. For HEXB VUSes, the rate of 34% in SD enzyme carriers was 12.3X higher than in individuals with normal enzyme levels. 30% of TSD and 22% of SD enzyme carriers did not show P/LP/PD variants or VUSes, a phenomenon that may be explained by benign variants with in vitro effects and/or other variants not uncovered by the NGS testing platform. CONCLUSION: Until the majority of VUSes are reclassified and additional sources of variation in the HEXA/HEXB genes are explored, there remains a role for Hex A enzyme assays in the identification of putative carriers and TSD/SD detection rates will remain higher for tests that include enzyme analysis.