Abstract
Background and Aims: Carrier screening for Tay-Sachs disease is performed by sequence analysis of the HEXA gene and/or hexosaminidase A enzymatic activity testing. Enzymatic analysis (EA) has been suggested as the optimal carrier screening method, especially in non-Ashkenazi Jewish (non-AJ) individuals, but its utilization and efficacy have not been fully evaluated in the general population. This study assesses the reliability of EA in comparison with HEXA sequence analysis in non-AJ populations. Methods: Five hundred eight Hispanic and African American patients (516 samples) had EA of their leukocytes performed and 12 of these patients who tested positive by EA (“carriers”) had subsequent HEXA gene sequencing performed. Results: Of the 508 patients, 25 (4.9%) were EA positive and 40 (7.9%) were inconclusive. Of the 12 patients who were sequenced, 11 did not carry a pathogenic variant and one carried a likely deleterious mutation (NM_000520.4(HEXA):c.1510C>T). Conclusions: High inconclusive rates and poor correlation between positive/inconclusive enzyme results and identification of pathogenic mutations suggest that ethnic-specific recalibration of reference ranges for EA may be necessary. Alternatively, HEXA gene sequencing could be performed.
Highlights
Tay-Sachs disease (TSD; MIM 272800), associated with mutations in HEXA, is a neurodegenerative disease caused by accumulation of GM2-ganglioside
Targeted mutation analysis is less effective for carrier detection in non-Ashkenazi Jewish (AJ) populations (Kaback et al, 1993), TSD does occur in other populations, including the French Canadian (Martin et al, 2007), Cajun (McDowell et al, 1992), Irish (Branda et al, 2004), and Italian (Montalvo et al, 2005) populations
Data were analyzed from 508 African/African American or Hispanic self-reported patients, who had screening between July 2013 and March 2014
Summary
Tay-Sachs disease (TSD; MIM 272800), associated with mutations in HEXA, is a neurodegenerative disease caused by accumulation of GM2-ganglioside. Individuals of Ashkenazi Jewish (AJ) ancestry have the highest TSD risk, due to a one in 31 carrier frequency (Gross et al, 2008). Carrier screening for Tay-Sachs disease is performed by sequence analysis of the HEXA gene and/or hexosaminidase A enzymatic activity testing. Enzymatic analysis (EA) has been suggested as the optimal carrier screening method, especially in non-Ashkenazi Jewish (non-AJ) individuals, but its utilization and efficacy have not been fully evaluated in the general population. Methods: Five hundred eight Hispanic and African American patients (516 samples) had EA of their leukocytes performed and 12 of these patients who tested positive by EA (‘‘carriers’’) had subsequent HEXA gene sequencing performed. Conclusions: High inconclusive rates and poor correlation between positive/inconclusive enzyme results and identification of pathogenic mutations suggest that ethnic-specific recalibration of reference ranges for EA may be necessary.
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