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

Abstract

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.

Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach

“…A recent study demonstrated that for both AJ and non-AJ populations, clinical performance of NGS-based CS was better than enzymatic methods to screen for Tay-Sachs. 31 Additional studies are needed to clarify whether the enzyme studies are still needed for rare variants. Similarly, screening for hemoglobinopathies has traditionally involved a complete blood count, red blood cell indices, reflex hemoglobin electrophoresis, and other testing if there is a suspicion of a hemoglobinopathy.…”

Equitable Expanded Carrier Screening Needs Indigenous Clinical and Population Genomic Data

“…8 It has been extremely effective, e.g., in reducing the incidence of Tay-Sachs disease (MIM: 272800) in Ashkenazi Jewish populations around the world. 9,10 ECS is an extension of this approach that involves simultaneous screening for many pathogenic variants responsible for a broad range of diseases in the general population. This broadscale approach to screening is achieved by sequencing the entire genomes (genome sequencing) or the fraction of the genome that encodes proteins-the exome (exome sequencing)-of prospective parents.…”

Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco

“…The activity of HEXA isoenzyme levels in TSD symptomatic individuals is deficient while that of β hexosaminidase B (HEXB) isoenzyme, is either normal or elevated. Therefore, an assessment of β hexosaminidase enzyme activity in peripheral leukocytes, cultured fibroblasts or lymphoblasts is the test widely used interna-tionally to diagnose the disease [4]. Recently, Next Generation Sequencing (NGS) has been proposed as an alternative screening method for TSD specially in populations with highly diverse ethnic origin.…”