Abstract
Biochemical testing of hexosaminidase A (HexA) enzyme activity has been available for decades and has the ability to detect almost all Tay-Sachs disease (TSD) carriers, irrespective of ethnic background. This is increasingly important, as the gene pool of those who identify as Ashkenazi Jewish is diversifying. Here we describe the analysis of a cohort of 4,325 individuals arising from large carrier screening programs and tested by the serum and/or platelet HexA enzyme assays and by targeted DNA mutation analysis. Our results continue to support the platelet assay as a highly effective method for TSD carrier screening, with a low inconclusive rate and the ability to detect possible disease-causing mutation carriers that would have been missed by targeted DNA mutation analysis. Sequence analysis performed on one such platelet assay carrier, who had one non-Ashkenazi Jewish parent, identified the amino acid change Thr259Ala (A775G). Based on crystallographic modeling, this change is predicted to be deleterious, as threonine 259 is positioned proximal to the HexA alpha subunit active site and helps to stabilize key residues therein. Accordingly, if individuals are screened for TSD in broad-based programs by targeted molecular testing alone, they must be made aware that there is a more sensitive and inexpensive test available that can identify additional carriers. Alternatively, the enzyme assays can be offered as a first tier test, especially when screening individuals of mixed or non-Jewish ancestry.
Competing interests: None declared
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Acknowledgments
We thank the Jonas Ehrlich Charitable Foundation for their generous support to the Carrier Testing Program at the Jacobi Human Genetics Laboratory, as well as the generous donors who subsidized the screening programs. We thank the National Tay-Sachs and Allied Diseases Association for their grant for HEXA sequence analysis. We thank Raffi Sturm for his early contributions to data analysis.
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Communicated by: Verena Peters
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Take Home Message
The platelet HexA enzyme assay is a highly effective method for Tay-Sachs disease carrier screening, with a low inconclusive rate and the ability to detect putative disease-causing carriers who would have been missed by targeted DNA mutation analysis alone.
Competing Interests
Steven Keiles and Anja Kammesheidt are employees and own stock in Ambry Genetics, and Tina Hambuch was also an employee there at the time of the study.
Authors’ Contributions
Sachiko Nakagawa • Jie Zhan • Wei Sun: directed the laboratory component of this study and generated all the cohort data under the direct supervision of SJG and NSA
Steven Keiles • Tina Hambuch • Anja Kammesheidt: responsible for the HEXA sequence analysis and mutation identification
Brian L. Mark: responsible for mutation modeling and interpretation
Adele Schneider : responsible for recruitment of participants and, in particular, the proband
Sachiko Nakagawa • Jose Carlos Ferreira • Susan Gross • Nicole Schreiber-Agus: interpreted the data and drafted and revised the article
Nicole Schreiber-Agus is the guarantor for the article
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Nakagawa, S. et al. (2012). Platelet Hexosaminidase A Enzyme Assay Effectively Detects Carriers Missed by Targeted DNA Mutation Analysis. In: JIMD Reports - Case and Research Reports, 2012/3. JIMD Reports, vol 6. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_120
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DOI: https://doi.org/10.1007/8904_2011_120
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