Crossed polydactyly type I caused by a point mutation in the GLI3 gene in a large Chinese pedigree

Polydactyly is one of the most common forms of congenital malformation in humans, and is displayed by 119 disorders. Crossed polydactyly (CP) is defined as the coexistence of preaxial and postaxial polydactyly with a difference in the axes of polydactyly between the hands and feet. In an effort to map the gene responsible for CP, we studied a seven-generation Chinese family of 56 individuals, 28 of whom were affected. A thorough search with highly informative polymorphic markers showed no recombination among the affected members with the markers on chromosome 7p15-q11.23, but no linkage with chromosomes 2q31, 7q36, 13q, and 19p. Mutation analysis showed a substitution mutation of 1927C --> T in exon 12 of the GLI3 gene, which is predicted to pretruncate the GLI3 protein. This mutation has variable phenotypes of polydactyly, indicating that other genetic factors also contribute to the diversity of polydactyly phenotypes. Our results increase the phenotypic spectrum caused by GLI3 mutations and are important for the analysis and understanding of the etiology of these limb malformations.