HOXD12 a candidate gene for a novel form of synpolydactyly

Synpolydactyly is a rare limb deformity characterized by a unique combination of syndactyly and polydactyly. Synpolydactyly has an autosomal dominant mode of inheritance often with reduced penetrance. Variants in HOXD13, FBLN1, GLI3, and TTC30B have been reported to underlie the etiology of synpolydactyly. Here, we describe a three-generational Pakistani family segregating a form of synpolydactyly which has not previously been reported that includes, severe hand involvement characterized by bilateral syndactyly of the third, fourth, and fifth fingers, accompanied by preaxial polydactyly in all affected family members. Synpolydactyly of the feet was absent and only one family member presented with unilateral syndactyly of the third, fourth, and fifth toes. Exome sequencing of DNA samples obtained from members of the family led to the identification of a missense variant in HOXD12 [NM_021193.4:c.512A>G, p.(Asn171Ser)] that segregates with the synpolydactyly. HOXD12 is expressed in the posterior half of developing limb and is involved in bone development by regulating digit formation and patterning. It has also been implicated in limb deformities in mice and humans. Although HOXD12 has been reported to be involved in the etiology of clubfoot, this is the first report of its involvement in etiology of synpolydactyly.