Advancing Tay Sachs Disease Carrier Screening: Insights from Combined Enzyme and Molecular Approaches

Tay-Sachs (TS) disease (MIM 272800) is an autosomal recessive neurodegenerative disorder caused by α subunit deficiency of β-hexosaminidase (Hexo A). Population based carrier screening for individuals of Ashkenazi Jewish ancestry by enzyme analysis successfully reduced the incidence of TS in US and Canada.

In a diverse, pan-ethnic population, Tay-Sachs carrier screening is endorsed by the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG). It typically employs both the Hexo enzyme assay and HEXA gene sequencing. Molecular testing can range from targeted variant to full-exon sequencing. The β-hexosaminidase enzyme assay, which measures lysosomal Hexo A and B enzymatic activities in leukocytes, has long been a cornerstone in Tay-Sachs screening.

In recent years, molecular screening panels have gained popularity, harnessing next-generation sequencing technology to cover a wide spectrum of diseases. Both enzyme analysis and molecular testing present challenges: Enzyme testing traditionally employs an artificial substrate and pseudodeficiency alleles result in carrier-range enzyme results despite not truly being a carrier of a pathogenic allele; DNA testing, particularly in diverse populations with low carrier frequency can identify variants of uncertain significance (VUS). Because of this VUS challenge, screening panels often report only selected variants, omitting potentially pathogenic novel variants.

To assess the utility of enzymatic carrier testing, we conducted a retrospective analysis of carrier sequencing results from our laboratory database. NGS carrier panel results were cross-referenced with leukocyte enzyme results. Any inconsistencies prompted retrieval of full HEXA sequence results for further variant curation. Results of total 44 patient results reported here support an integrated approach employing both molecular and enzymatic testing in Tay Sachs carrier screening to improve carrier detection