X-linked hypohidrotic ectodermal dysplasia: localization within the region Xq11-21.1 by linkage analysis and implications for carrier detection and prenatal diagnosis.

X-linked hypohidrotic ectodermal dysplasia (H.E.D.) is a disorder of abnormal morphogenesis of ectodermal structures and is of unknown pathogenesis. Neither relatively accurate carrier detection nor prenatal diagnosis has been available. Previous localization of the disorder by linkage analysis utilizing restriction-fragment polymorphisms, by our group and others, has placed the disorder in the general pericentromeric region. We have extended our previous study by analyzing 36 families by means of 10 DNA probes at nine marker loci and have localized the disorder to the region Xq11-Xq21.1, probably Xq12-Xq13. Three loci--DXS159 (theta = .01, z = 14.84), PGK1 (theta = .02, z = 13.44), and DXS72 (theta = .02, z = 11.38)--show very close linkage to the disorder, while five other pericentromeric loci (DXS146, DXS14, DXYS1, DXYS2, and DXS3) display significant but looser linkage. Analysis of the linkage data yields no significant evidence for nonallelic heterogeneity for the X-linked form of the disorder. Both multipoint analysis and examination of multiply informative meioses with known phase establish that the locus for H.E.D. is flanked on one side by the proximal long arm loci DXYS1, DXYS2, and DXS3 and on the other side by the short arm loci DXS146 and DXS14. Multipoint mapping could not resolve the order of H.E.D. and the three tightly linked loci. This order can be inferred from published data on physical mapping of marker loci in the pericentromeric region, which have utilized somatic cell hybrid lines established from a female with severe manifestations of H.E.D., and an X/9 translocation (breakpoint Xq13.1). If one assumes that the breakpoint of the translocation is within the locus for H.E.D. and that there has not been a rearrangement in the hybrid line, then DXS159 would be proximal to the disorder and PGK1 and DXS72 would be distal to the disorder. Both accurate carrier detection and prenatal diagnosis are now feasible in a majority of families at risk for the disorder.