Section 10
Chapter 9,068

Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of French Canadian background living in New England

Triggs-Raine, B.; Richard, M.; Wasel, N.; Prence, E.M.; Natowicz, M.R.

American Journal of Human Genetics 56(4): 870-879


ISSN/ISBN: 0002-9297
PMID: 7717398
Accession: 009067314

Tay-Sachs disease (TSD) results from mutations in HEXA that cause Hex A deficiency. Heterozygote-screening programs have been applied in groups with an increased TSD incidence, such as Ashkenazi Jews and French Canadians in Quebec. These programs are complicated by benign mutations that cause apparent Hex A deficiency but not TSD. Benign mutations account for only apprx 2% of jewish and apprx 36% of non-jewish enzyme-defined carriers. A carrier frequency of 1/53 (n = 1,434) was found in an ongoing prospective analysis of persons of French Canadian background living in New England by using an enzyme-based assay. DNA from enzyme-defined carriers from this population was analyzed to determine the molecular basis of Hex A deficiency. Samples (36) were tested for common mutations, and samples that were negative for these were screened for uncommon or novel mutations by using SSCP analysis. Exons showing mobility shifts were sequenced, and most mutations were confirmed by restriction enzyme digestion. Known disease-causing mutations were found in nine samples (four had a 7.6-kb deletion found in 80% of French Canadian TSD alleles), and known benign mutations were found in four samples. Seven novel changes were identified, including G748A in four samples. The molecular basis of Hex A deficiency in this carrier population differs from that of French Canadian TSD patients. Screening centers should be aware of the presence of benign mutations among U.S. French Canadians or Franco-Americans. Although the clinical significance of the novel mutations is unknown, the frequency of the G748A mutation, and the fact that it has not been detected in a TSD patient, suggests that it too may be benign.

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