We recently assigned the gene for cartilage-hair hypoplasia (CHH) to chromosome 9 in Finnish families. Here we have extended and refined our previous linkage analyses by studying 22 Amish and 15 Finnish CHH families and by testing additional markers. The CHH gene maps to 9p in both series and shows no evidence of heterogeneity either within or between the populations. CHH is very closely linked to marker locus D9S163, with no recombinations observed and a combined maximum multipoint lod score of 26.30 for a location at D9S163. Although the odds against a location of the CHH gene between two more distal marker loci, D9S52 and D9S165, are only 48:1, the evidence provided by an observed recombination between the CHH locus and D9S165 and haplotype data at D9S165 and D9S163 in the Amish families allow this interval to be excluded as the location of CHH. We observed strong allelic association between CHH and D9S163 in both Amish and Finnish families, confirming the likely location of the CHH gene very close to this marker. Haplotype analysis of D9S163 and D9S165 in the Amish families suggests that only one mutation accounts for most CHH cases among them, as was expected and as is the case in Finland. Our data do not support the previously suggested hypothesis of a reduced penetrance as an explanation for the deficiency of affected children in the Amish families. We conclude that CHH is a single disease entity in the Amish and Finnish families and that the CHH gene is very close to D9S163 in 9p21-p13.
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