Broadening the Mutation Spectrum in GJA8 and CHMP4B: Novel Missense Variants and the Associated Phenotypes in Six Chinese Han Congenital Cataracts Families

Purpose: To broaden the mutation and phenotype spectrum of the GJA8 and CHMP4B genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs).Methods: Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins.Results: Four heterozygous candidate variants in three different genes (CRYBB2, GJA8, and CHMP4B) were identified in affected individuals from the six families, including two novel missense variants (GJA8: c.64G > C/p. G22R, and CHMP4B: c.587C > G/p. S196C), one missense mutation (CRYBB2: c.562C > T/p. R188C), and one small deletion (GJA8: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the GJA8: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts.Conclusion: This study further expands the mutation spectrum and genotype-phenotype correlation of CRYBB2, GJA8, and CHMP4B underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants