Complex postaxial polydactyly types A and B with camptodactyly, hypoplastic third toe, zygodactyly and other digit anomalies caused by a novel GLI3 mutation.

Polydactyly is a phenotypically and genetically highly heterogeneous limb malformation with preaxial and postaxial subtypes and subtypes A and B. Most polydactyly entities are associated with GLI3 mutation. We report on 10 affected individuals from a large Pakistani kindred initially evaluated as a possible new condition. The phenotype is postaxial polydactyly types A and B associated with zygodactyly, postaxial webbing of toes and additional features not previously reported for isolated polydactyly such as camptodactyly, hypoplasia of third toe, and wide space between hallux and second toe. Hypothesizing that the disorder could have resulted from a mutation in a novel gene responsible for polydactyly, we launched a genetic investigation. By linkage mapping and exome sequencing in the most severe case, we identified novel heterozygous frameshift mutation NM_000168.5 (GLI3): c.3635delG (p.(Gly1212Alafs*18)) but did not detect any other possibly deleterious mutation that could explain the unusual features of camptodactyly, hypoplasia of third toe and wide space between first and second toes. Our findings further expand the phenotypic variability of GLI3 polydactyly. We also present a review of GLI3-associated isolated limb anomalies, which indicates that GLI3 mutation leads primarily to two well-established polydactyly types: postaxial types A and B and crossed polydactyly type I. In addition, a variety of other minor digit anomalies generally accompany polydactyly, and there is no straightforward genotype-polydactyly phenotype correlation.