gms | German Medical Science

Objectives/Interrogation: Polydactyly is a genetically and phenotypically heterogeneous disorder which is the third most frequent congenital anomaly in China. The purpose of this study was to systemically investigate the genotype-phenotype correlations of familial polydactyly in Chinese people.

Methods: A total of 18 Chinese families with polydactyly were included. The family histories were recorded and physical examination of available family members was performed. Genomic DNA was prepared from peripheral blood of affected and unaffected individuals. Whole exome sequencing, Sanger sequencing, CytoScan and qPCR were used to identify the pathogenic mutations. The genotype-phenotype correlations were analyzed. Variants were functionally assessed by luciferase assay or computational simulation.

Results and Conclusions: Pathogenic mutations within HOXD13 and GLI3 were predominantly identified in 17 out of 18 families (94%). Among 11 families with HOXD13 mutations, 10 families had a 7- to 9-alanine expansion of the N-terminal 15-mer poly-alanine region spanning amino acids 57 to 72, and the other one family had a single amino acid substitution, I309F, in the conserved homeobox domain. GLI3 mutated in 6 families, all of which were truncating mutations. Phenotypically, preaxial polydactyly of either hands or feet, frequently Wassel type II and IV, and postaxial polydactyly of the hands were exclusively found in GLI3 mutated families, while postaxial polysyndactyly of the feet was unique for HOXD13 mutated families. In addition, synpolydactyly of 3/4 fingers and 4/5 toes was exclusively associated with HOXD13 mutations, but in GLI3 mutated families, syndactyly could happen between any of two digits and frequently involved multiple digits. Finally, clinodactyly of 4th or 5th fingers and broad thumbs were additional unique feature for HOXD13 and GLI3 mutated families, respectively. Functionally, I309F impairs HOXD13 transcription activity. In conclusion, through the molecular genetics study of the largest cohort of familial polydactyly of Chinese people, we revealed that GLI3 and HOXD13 were predominant mutated genes. Preaxial polydactyly of hands or feet, postaxial polydactyly of the hands, and broad thumbs were exclusively associated with GLI3 mutations, while synpolydactyly of 3/4 fingers or 4/5 toes, and clinodactyly of 4th or 5th finger were unique for HOXD13 mutations. Sanger sequencing of GLI3 or HOXD13 according to specific manifestation could be a cost-effective genetic diagnosis method for patients with polydactyly.