MUTATIONAL ANALYSES OF TAY-SACHS-DISEASE - STUDIES ON TAY-SACHS CARRIERS OF FRENCH-CANADIAN BACKGROUND LIVING IN NEW-ENGLAND

Tay-Sachs disease (TSD) results from mutations in HEXA that cause Hex A deficiency. Heterozygote-screening programs have been applied in gro ups with an increased TSD incidence, such as Ashkenazi Jews and French Canadians in Quebec. These programs are complicated by benign mutatio ns that cause apparent Hex A deficiency but not TSD. Benign mutations account for only similar to 2% of Jewish and similar to 36% of non-Jew ish enzyme-defined carriers. A carrier frequency of 1/53 (n = 1,434) w as found in an ongoing prospective analysis of persons of French Canad ian background living in New England by using an enzyme-based assay. D NA from enzyme-defined carriers from this population was analyzed to d etermine the molecular basis of Hex A deficiency. Samples (36) were te sted for common mutations, and samples that were negative for these we re screened for uncommon or novel mutations by using SSCP analysis. Ex ons showing mobility shifts were sequenced, and most mutations were co nfirmed by restriction enzyme digestion. Known disease-causing mutatio ns 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 foun d in four samples. Seven novel changes were identified, including G748 A in four samples. The molecular basis of Hex A deficiency in this car rier population differs from that of French Canadian TSD patients. Scr eening centers should be aware of the presence of benign mutations amo ng U.S. French Canadians or Franco-Americans. Although the clinical si gnificance of the novel mutations is unknown, the frequency of the G74 8A mutation, and the fact that it has not been detected in a TSD patie nt, suggests that it too may be benign.