In affected members of a 4-generation family with mild features of classic synpolydactyly (SPD1; 186000), Debeer et al. (2002) identified an 892C-T transition in the HOXD13 gene, resulting in an arg298-to-trp (R298W) mutation in the homeodomain of the protein. As arg298 is the thirty-first residue of the HOXD13 homeodomain, the authors referred to this mutation as ARG31TRP. The mutation was thought to destabilize the homeodomain-DNA complex. The digital abnormalities it produced closely resembled those produced by frameshifting deletions in HOXD13. Only 3 of 17 mutation carriers in the family had synpolydactyly, and in all 3 this was unilateral only, whereas none had synpolydactyly in the feet. However, affected members did have partial duplication of the second metatarsals, broad halluces, and hypoplasia or symphalangism of the middle phalanges of the foot. In 13, the only finding was bilateral fifth finger clinodactyly, raising the possibility that some patients with dominantly inherited isolated fifth finger clinodactyly (type A3 brachydactyly; 112700) may harbor mutations in HOXD13. One mutation carrier in the 4-generation family married a member of another family in which hand-foot-genital syndrome (140000) was caused by a polyalanine tract expansion in the HOXA13 gene (142959.0007). The couple produced a girl heterozygous for both mutations who had digital abnormalities strikingly more severe than those in carriers of either individual mutation, indicating that the 2 mutations acted synergistically.