Screening the pathogenic causes of congenital cataract via whole exome sequencing technology in three families: Molecular genetics of congenital cataract

Congenital cataract is the commonest cause of visual impairment and blindness in children worldwide. Among congenital cataract cases, similar to 25% are caused by genetic defects, while several genetic mutations have been identified in hereditary cataract. In the present study, a patient with cataract underwent clinical ophthalmic examination and pedigree analysis. Whole exome sequencing and Sanger sequencing were performed to identify and verify gene mutations. The frequency, conservation, pathogenicity and hydrophobicity of the mutated amino acids were analyzed by bioinformatics analysis. The clinical examination and investigation verified that the probands of family A and C suffered from nuclear cataracts. In addition, the proband of family B was diagnosed with white punctate opacity. The pattern of inheritance was autosomal dominant. The sequencing analysis results revealed a mutation c.592-c593insG (p.W198Wfs*22) in exon 6 of CRYBA1/A3, a known mutation c.463C > T (p.Q155X) in exon 6 of CRYBB2 and a third mutation c.865-c.866insC (p.T289Tfs*91) in exon 2 of GJA8. Each variant was co-segregated with disease in family And the mutation frequency in the database was <0.01. It has been reported that the mutation sites are highly conserved among different species, thus greatly affecting the sequence and structure of a protein, while exhibiting high pathogenicity in theory. The two crystallin gene mutations could notably enhance the local hydrophobicity of the protein, eventually resulting in its reduced solubility and destruction of lens transparency. The current study identified pathogenic genes in three families with congenital cataract and analyzed the association between mutation sites and different cataract phenotypes. Overall, the results could expand the genotype spectrum of congenital cataract and provide evidence for its clinical diagnosis.

Automated summary

Congenital cataract is a common cause of visual impairment and blindness in children, with a significant portion attributed to genetic defects. This study identified and verified gene mutations in patients with cataract using clinical examination and genetic sequencing analysis. The identified mutations in CRYBA1/A3 and CRYBB2 genes were found to affect the protein structure and hydrophobicity, leading to reduced solubility and lens transparency. These findings expand the understanding of the genetic spectrum of congenital cataract and have implications for clinical diagnosis.