Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. W e have therefore examined HOXA13 in two new and four previously reported fa milies with features of HFGS. In families 1, 2, and 3, nonsense mutations t runcating the encoded protein N-terminal to or within the homeodomain produ ce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an excep tionally severe limb phenotype; and in family 6, in which limb abnormalitie s were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspecte d and may act by more than one mechanism.