The French Canadian Tay-Sachs disease deletion mutation: identification of probable founders.

Tay-Sachs disease (TSD) is an inherited neurodegenerative ganglioside storage disorder caused by deficiency of the hexosaminidase A enzyme. A deletion allele (FCD) at the HEXA locus has attained high frequency in the French Canadian population. The distribution of affected probands shows a likely center of diffusion for this mutation located in the Bas-St.-Laurent and Gaspésie regions of the province of Quebec. We have reconstructed the genealogies of 15 obligate carriers of the FCD allele to an average depth of 12 generations identifying 60 ancestors and 80 European founders common to all of them. The ancestral origins of the European founders show a significantly greater number of individuals born in the French provinces of Normandy and Perche than expected based on information regarding the origins of the 8,500 immigrants who settled the colony of New France during the French regime. We have identified common ancestors among the 10 who were born in Quebec who appear to be likely candidates for the origin of the FCD mutation. One such couple had 11 children, 5 of whom settled in regions of Quebec or New Brunswick that today have elevated heterozygote frequencies for the FCD. The five offspring are ancestors of all known carriers. By contrast, the absence of FCD alleles among TSD probands in France suggests that the mutation did not occur in a European founder.