Screening for Tay‐Sachs disease carriers by full‐exon sequencing with novel variant interpretation outperforms enzyme testing in a pan‐ethnic cohort

摘要

BackgroundPathogenic 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.