Fine mapping of the split-hand/split-foot locus (SHFM3) at 10q24: Evidencefor anticipation and segregation distortion

Split-hand/split-foot malformation (SHFM, ectrodactyly, or lobster-claw def ormity) is a:human limb malformation characterized by aberrant development of central digital rays with absence of fingers and toes, a deep median cle ft, and fusion of remaining digits. SHFM is clinically heterogeneous, prese nting both in an isolated form and in combination with additional abnormali ties affecting the tibia and/or other organ systems, including the genitour inary, craniofacial, and ectodermal structures. Three SHFM disease loci hav e been genetically. mapped to chromosomes 7q21 (SHFM1), Xq26 (SHFM2), and 1 0q24 (SHFM3). We mapped data from a large Turkish family with isolated SHFM to chromosome 10q24 and have narrowed the SHFM3 region from 9 cM to an sim ilar to 2-cM critical interval between genetic markers D10S1147 and D10S124 0. In several instances we found evidence for a more severe phenotype in of fspring of a mildly affected parent, suggesting anticipation. Finally, data from this family, combined with those from six other pedigrees, mapped to 10q24, demonstrate biased transmission of SHFM3 alleles from affected fathe rs to offspring. The degree of this segregation distortion is obvious in ma le offspring and is possibly of the same magnitude for female offspring.