A novel GJA1 mutation identified by whole exome sequencing in a Chinese family with autosomal dominant syndactyly

Syndactyly is one of the most common hereditary limb malformations characterized by fusion of adjacent fingers and/or toes. The current classification scheme of non-syndromic syndactyly defines at least nine well-characterized syndactylous entities with subdivisions based on phenotype and genotype. Here, we reported a 3-generation Chinese pedigree with four affected Syndactyly members inherited in an autosomal dominant manner. We performed whole exome sequencing on two affected members and successfully identified a novel missense mutation p.R101L in GJA1 as the pathogenic mutation. The manifestations caused by GJA1 R101L mutation are different from typical characteristics of oculodentodigital dysplasia. Connexin 43 (Cx43), encoded by GJA1, plays a key role in normal facial and limb development. Arg101Leu mutation caused a hydrophobic to hydrophilic substitution, changing the structural integrity and stability of the molecule. Three-dimensional structural analysis showed this mutation could alter the conformation of residue side chain and produce steric clashes with spatial adjacent residues and cause folding destabilization, suggesting this amino acid appears to play an important role in the structure and function of Cx43. Our study also demonstrates the power of whole exome sequencing in causal mutation identification for phenotypically variable and genetically heterogeneous disorders.