Terminal osseous dysplasia with pigmentary defects maps to human chromosome Xq27.3-Xqter

We have identified a four-generation family with 10 affected females manife sting one or more of the following features: osseous dysplasia involving th e metacarpals, metatarsals, and phalanges leading to brachydactyly, camptod actyly, and other digital deformities; pigmentary defects on the face and s calp; and multiple frenula. There were no affected males. We performed X-in activation studies on seven affected females, using a methylation assay at the androgen receptor locus; all seven demonstrated preferential inactivati on of their maternal chromosomes carrying the mutation, and two unaffected females showed a random pattern. These findings indicate that this disorder is linked to the X chromosome. To map the gene for this disorder, we analy zed DNA from nine affected females and five unaffected individuals, using 4 0 polymorphic markers evenly distributed throughout the X chromosome. Two-p oint and multipoint linkage analyses using informative markers excluded mos t of the X chromosome and demonstrated linkage to a region on the long arm between DXS548 and Xqter. A maximum LOD score of 3.16 at recombination frac tion 0 was obtained for five markers mapping to Xq27.3-Xq28. The mapping da ta should facilitate the identification of the molecular basis of this diso rder.