A Novel Frameshift Mutation of GLI3 Causes Isolated Postaxial Polydactyly

GLI3 encodes a transcription factor in the sonic hedgehog signaling pathway, which is essential in regulating the human limb bud development, especially on the anteroposterior axis. Mutations in GLI3 have been confirmed to be associated with various human congenital malformations, including Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and isolated polydactyly. A robust gene-phenotype relationship between GLI3 and Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome has been well elucidated, and less is known about GLI3 mutation-caused isolated polydactyly. This study intended to perform a mutation analysis of GLl3 in a family with isolated polydactyly.

A 3-generation Chinese family with 19 members was recruited in this study, of which the proband and her mother were affected with polydactyly. The whole-exon sequencing was performed to find mutations, and Sanger sequencing was performed to validate the mutations.

We found a novel heterozygous frameshift mutation of GLI3 (c.1180C > TT, p.P394fs18x) in the proband of a Chinese family with isolated postaxial polydactyly. No mutation was detected in the proband's father or another 2 patients with sporadic preaxial polydactyly.

By systematically reviewing the gene-phenotype relationship, we found that GLI3 p.P394fs18x mutation might be specific for isolated postaxial polydactyly.