SYNPOLYDACTYLY PHENOTYPES CORRELATE WITH SIZE OF EXPANSIONS IN HOXD13POLYALANINE TRACT

Synpolydactyly (SPD) is a dominantly inherited congenital limb malform ation. Typical cases have 3/4 finger and 4/5 toe syndactyly, with a du plicated digit in the syndactylous web, but incomplete penetrance and variable expressivity are common. The condition has recently been show n to be caused by expansions of an imperfect trinucleotide repeat sequ ence encoding a 15-residue polyalanine tract in HOXD13. We have studie d 16 new and 4 previously published SPD families, with between 7 and 1 4 extra residues in the tract, to analyze the molecular basis for the observed variation in phenotype. Although there is no evidence of chan ge in expansion size within families, even over six generations, there is a highly significant increase in the penetrance and severity of ph enotype with increasing expansion size, affecting both hands (P = 0.01 2) and feet (P < 0.00005). Affected individuals from a family with a 1 4-alanine expansion, the largest so far reported, all have a strikingl y similar and unusually severe limb phenotype, involving the first dig its and distal carpals. Affected males from this family also have hypo spadias, not previously described in SPD, but consistent with HOXD13 e xpression in the developing genital tubercle. The remarkable correlati on between phenotype and expansion size suggests that expansion of the tract leads to a specific gain of function in the mutant HOXD13 prote in, and has interesting implications for the role of polyalanine tract s in the control of transcription.