Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping

HED is an autosomal dominant skin disorder that is particularly common in t he French Canadian population of south-west Quebec. We previously mapped th e HED gene to the pericentromeric region of chromosome 13q using linkage an alysis in eight French Canadian families. In this study, we extend our gene tic analysis to include a multiethnic group of 29 families with 10 polymorp hic markers spanning 5.1 cM in the candidate region. Two-point linkage anal ysis strongly suggests absence of genetic heterogeneity in HED in four fami lies of French, Spanish, African and Malaysian origins. Multipoint linkage analysis in all 29 families generated a peak lod score of 53.5 at D13S1835 with a 1 lod unit support interval spanning 1.8 cM. Recombination mapping p laced the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D1 3S1830 distally. We next show evidence for a strong founder effect in famil ies of French Canadian origin thereby representing the first example of a f ounder disease in the south-west part of the province of Quebec. Significan t association was found between HED in these families and all markers analy sed (Fisher's exact test, P < 0.001). Complete allelic association was dete cted at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P-excess = 1) sp anning 1,3 cM. A major haplotype including all 10 associated alleles was pr esent on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Can adian population. Luria-Delbruck equations and multipoint likelihood linkag e disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support int erval: 3.27 cM) respectively.