Abstract
Purpose: To compare the sensitivity of Hexosaminidase A (HexA) enzyme-based testing to gene sequencing for carrier detection in non-Jewish individuals. Methods: Blood samples were obtained from parents and relatives of affected patients at an annual Tay-Sachs and Allied Diseases Foundation meeting. A family history was taken for each individual. Samples were analyzed for leukocyte HexA activity, serum HexA activity and subjected to extensive gene sequencing. The results from these analyses were combined with our previously published data describing 34 obligate Tay-Sachs disease (TSD) carriers. Results: Twelve additional TSD carriers were detected in this study. Gene sequencing successfully identified all 12 carriers whereas enzyme analysis identified 11 of 12 carriers. This individual is a carrier of the B1 variant that is known to cause false negative results with enzyme testing. Combined data from 46 non-Jewish TSD carriers revealed that gene sequencing had a higher sensitivity rate than HexA enzyme-based testing (94% versus 87%) in non-Jewish TSD carriers. In our series, approximately 4% of non-Jewish TSD carriers have this mutation. Conclusions: HexA gene sequencing provides a higher sensitivity for TSD carrier detection than HexA based enzyme analysis in non-Jewish patients primarily due to the presence of individuals with the B1 variant.
Highlights
As automation and technical improvements continue to drive down the costs of DNA sequencing, it has become feasible to perform Hex A gene sequencing as a primary screening test for Tay-Sach’s Disease (TSD) carrier detection
This study enlarges upon an earlier study that demonstrated that sequencing and enzyme analysis had identical sensitivities in identifying Tay-Sachs disease (TSD) carriers to determine whether DNA sequencing would be an appropriate initial screen for non-Ashkenazi Jewish (AJ) individuals
Combining the data from this study and the previous study [11]. demonstrates that for the individuals tested in these 2 studies, extensive gene sequencing has a higher sensitivity than enzyme analysis for TSD carrier detection
Summary
As automation and technical improvements continue to drive down the costs of DNA sequencing, it has become feasible to perform Hex A gene sequencing as a primary screening test for Tay-Sach’s Disease (TSD) carrier detection. This study enlarges upon an earlier study that demonstrated that sequencing and enzyme analysis had identical sensitivities in identifying TSD carriers to determine whether DNA sequencing would be an appropriate initial screen for non-Ashkenazi Jewish (AJ) individuals. Tay-Sachs disease, or GM2 Gangliosidosis, is an autosomal recessive neurodegenerative disorder caused by a deficiency of beta-hexosaminidase A (HexA), resulting in lysosomal accumulation of GM2 ganglioside. Tay-Sachs disease can first manifest symptoms in adulthood and is called late onset TSD or LOTS. Even in LOTS there is a progressive of symptoms are progression eventually resulting in profound disability [1]
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