The heterozygous c.2241G>C variation in FGFR2 may cause autosomal dominant Kirner's deformity in a Chinese Han pedigree.

objectiveKirner’s deformity is a progressive deformity of the distal phalange of the little finger in a volar and radial direction. The FGFR2 gene plays a critical role in skeletal development and growth, with abnormal expression and activation of FGFR2 being associated with skeletal abnormalities. This study presents a family with Kirner’s deformity involving multiple patients.

methodsWhole-exome sequencing was performed. SIFT, MutationTaster and Gerp+, while Clustal Omega was used for conservative analysis. In addition, I-TASSER was used to predict the 3D protein model. PyMOL was used for comparative analysis between abnormal and normal proteins.

resultsSequencing data revealed that the proband, affected father, and son all carried a heterozygous missense variation c.2241G>C (p. Q747H) in FGFR2. Bioinformatic analysis suggested the potential pathogenicity of this variation. While the spatial structure of the protein variant was not significantly altered, the FGFR2 variation (p.Q747H) disrupted a hydrogen bond between Gln 747 and Ser 746, leading to significant changes in ligand and enzyme binding active sites. This structural alteration is predicted to impair binding to the Mg2+ ligand, thereby potentially disrupting downstream signaling pathways. This proposed mechanism provides a plausible explanation for the observed abnormal expression of bone development genes.

conclusionThese findings are consistent with a model in which the novel FGFR2 variant could impair protein function, a hypothesis that warrants further investigation. Our study identifies a new variant in the variational spectrum of Kirner’s deformity and expands the variational spectrum of the FGFR2 gene.