EVIDENCE FOR LOCUS HETEROGENEITY IN HUMAN AUTOSOMAL-DOMINANT SPLIT HAND SPLIT FOOT MALFORMATION

Split hand/split foot (SHSF; also known as ectrodactyly) is a human de velopmental disorder characterized by missing central digits and other distal limb malformations. An association between SHSF and cytogeneti cally visible rearrangements of chromosome 7 at bands q21-q22 provides compelling evidence for the location of a causative gene at this loca tion, and the locus has been designated SHFD1. In the present study, m arker loci were localized to the SHFD1 critical region through the ana lysis of somatic cell hybrids derived from individuals with SHSF and c ytogenetic abnormalities involving the 7q21-q22 region. Combined genet ic and physical data suggest that the order of markers in the SHFD1 cr itical region is 2-D7S527-(D7S473-D7S491)-SHFD1-D7S554-D7S518-qter. Di nucleotide repeat polymorphisms at three of these loci were used to te st for linkage of SHSF to this region in a large pedigree that demonst rates autosomal dominant SHSF. Evidence against linkage of the SHSF ge ne to 7q21-q22 was obtained in this pedigree. Therefore, combined mole cular and genetic data provide evidence for locus heterogeneity in aut osomal dominant SHSF. We propose the name SHSF2 for this second locus.