ClinVar Genomic variation as it relates to human health

On the basis of study of 2 Ashkenazi patients and 2 French Canadian patients with a Hex-A cDNA probe, Myerowitz and Hogikyan (1986) concluded that each of these populations has a different mutation. In the Ashkenazi mutation the HEXA gene appeared to be intact, whereas in the French Canadian mutation the gene had a 5-prime deletion of 5 to 8 kilobases. The disorders are clinically identical and the heterozygote frequency in each is the same. It had previously been suspected that the Ashkenazi gene was introduced into the French Canadian population by someone, presumably male, of Ashkenazi extraction (the 'Jewish fur trader hypothesis'). Keats et al. (1987) suspected that the mutation in French Canadians may be different from that in Ashkenazi Jews because the ratio HEXA/(HEXA + HEXB) was not a satisfactory statistic for carrier status in the French Canadian population whereas it is in Ashkenazi Jews. Myerowitz and Hogikyan (1987) showed that the deletion in the French Canadian form of Tay-Sachs disease (272800) is 7.6 kb long, includes part of intron 1 and all of exon 1, and extends 2,000 bp upstream past the putative promoter region of the alpha-chain gene. Sequence analysis of the deletion junction in the mutant gene and corresponding regions of the normal gene demonstrated the presence of similarly oriented Alu sequences at the 5-prime and 3-prime deletion boundaries. Myerowitz and Hogikyan (1987) interpreted this as indicating that the deletion had arisen during homologous recombination and unequal crossing-over between Alu sequences. Hechtman et al. (1990) found the 7.6-kb deletion mutation at the 5-prime end of the HEXA gene in 18 of 22 independently segregating mutant chromosomes from patients of French Canadian origin. One chromosome carried the 4-nucleotide insertion in exon 11 (606869.0001). None of the chromosomes carried the 5-prime splice site mutation in intron 12 found in Ashkenazi Jews (606869.0002). One chromosome carried a 'novel,' but not yet characterized type of B1 mutation. The remaining 3 patients carried TSD alleles different from all of the above-mentioned ones. In French Canadians, the 5-prime deletion clustered in persons originating in southeastern Quebec (Gaspe) and adjacent counties of northern New Brunswick. De Braekeleer et al. (1992) traced the ancestry of the persons carrying the 'French Canadian deletion' 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 showed 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 New France during the French regime. The failure to find the French Canadian deletion among TSD probands in France suggests that the mutation occurred on Canadian soil. If this is true, the search for the ancestral couple was narrowed to 7 possibilities. These included a man born in 1680 and his wife born in 1683, who had 11 offspring, at least 5 of whom must have been heterozygous for the deletion because they had carrier descendants through a total of 14 descendant lines. (less)