TY - JOUR
T1 - Clouston hidrotic ectodermal dysplasia (HED)
T2 - Genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping
AU - Kibar, Zoha
AU - Dubé, Marie Pierre
AU - Powell, Julie
AU - McCuaïg, Catherine
AU - Hayflick, Susan J.
AU - Zonana, Jonathan
AU - Hovnanian, Alain
AU - Radhakrishna, Uppala
AU - Antonarakis, Stylianos E.
AU - Benohanian, Antranik
AU - Sheeran, Amy D.
AU - Stephan, Mark L.
AU - Gosselin, Richard
AU - Kelsell, David P.
AU - Christianson, Arnold L.
AU - Clarke Fraser, F.
AU - Der Kaloustian, Vazken M.
AU - Rouleau, Guy A.
N1 - Funding Information:
We would like to thank the families that made this study possible. This work was supported by grants from the Canadian Dermatology Foundation (GAR), the National Foundation for Ectodermal Dysplasias (GAR and JZ) and NIDR DE11311 (JZ). GAR is supported by the Medical Research Council of Canada.
PY - 2000/5
Y1 - 2000/5
N2 - HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families 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 placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbruck equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively.
AB - HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families 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 placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbruck equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively.
KW - Founder effect
KW - French Canadian population
KW - Genetic homogeneity
KW - Genetic mapping
KW - Hidrotic ectodermal dysplasia
KW - Linkage disequilibrium analysis
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U2 - 10.1038/sj.ejhg.5200471
DO - 10.1038/sj.ejhg.5200471
M3 - Article
C2 - 10854098
AN - SCOPUS:17044441365
SN - 1018-4813
VL - 8
SP - 372
EP - 380
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 5
ER -