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

ABSTRACT: 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC8554029 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Congenital cataract, a kind of cataract presenting at birth or during early childhood, is a leading cause of childhood blindness. To date, more than 30 genes on different chromosomes are known to cause this disorder. This study aimed to identify the HSF4 mutations in a cohort from Chinese families affected with congenital cataracts. METHODS:Forty-two unrelated non-syndromic congenital cataract families and 112 ethnically matched controls from southeast China were recruited from the southeast of China. We employed Sanger sequencing method to discover the variants. To confirm the novel mutations, STR haplotypes were constructed to check the co-segregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools including SIFT, Polyphen2, and Human Splicing Finder. The pathogenicity of all the mutations was evaluated by the guidelines of American College of Medical Genetics and InterVar software. RESULTS:No previously reported HSF4 mutations were found in all the congenital cataract families. Five novel HSF4 mutations including c.187 T?>?C (p.Phe63Leu), c.218G?>?T (p.Arg73Leu), c.233A?>?G (p.Tyr78Cys), IVS5 c.233-1G?>?A and c.314G?>?C (p.Ser105Thr) were identified in five unrelated families with congenital cataracts, respectively. These mutations co-segregated with all affected individuals in each family were not observed in the unaffected family members or in 112 unrelated controls. All five mutations were categorized to be the disease "pathogenic" according to ACMG guidelines and using InterVar software. Mutations in the HSF4 were responsible for 11.90% Chinese families with congenital cataracts in our cohort. CONCLUSIONS:In the study, we identified five novel HSF4 mutations in Chinese families with congenital cataracts. Our results expand the spectrum of HSF4 mutations causing congenital cataracts, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine.

Project description:Purpose:To identify mutations in crystallin genes in Chinese families with congenital cataracts. Methods:Forty-two unrelated families with non-syndromic congenital cataracts were enrolled in this study. The coding exons and adjacent intronic regions of crystallin genes, including CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD and CRYGS, were analyzed with Sanger sequencing. Novel variants were further evaluated in 112 ethnically matched controls. To confirm the novel mutations, short tandem repeat (STR) haplotypes were constructed to check the cosegregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools, including Sorting Intolerant From Tolerant v5.1.1 (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Human Splicing Finder. The pathogenicity of all the mutations was evaluated according to the guidelines of the American College of Medical Genetics (ACMG) and InterVar software. Results:Seven previously reported mutations in crystallin genes identified in ten unrelated families were associated with the congenital nuclear cataracts. Four novel mutations in crystallin genes, including c.35G>T (p.R12L) in CRYAA, c.463C>A (p.Q155K) in CRYBB2, IVS1 c.10-1G>A in CRYGC, and c.346delT (p.F116Sfsx29) in CRYGD, were identified in four unrelated families with congenital cataracts. These mutations cosegregated with all affected individuals in each family were not observed in the unaffected family members or in the 112 unrelated controls. All four novel mutations were categorized as disease "likely pathogenic" except IVS1 c.10-1G>A in CRYGC "pathogenic" using InterVar software in accordance with the ACMG standard. Mutations in crystallin genes were responsible for 33.33% of the Chinese families with congenital cataracts in this cohort. Conclusions:In this study, we identified four novel mutations in crystallin genes in Chinese families with congenital cataracts. The results expand the mutational spectrum of crystallin genes, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine.

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

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