Dataset Information

Mutational screening of six genes in Chinese patients with congenital cataract and microcornea.

ABSTRACT: PURPOSE: To identify mutations in 6 genes of 9 Chinese families with congenital cataract and microcornea. METHODS: Nine unrelated families with congenital cataract and microcornea were collected. Cycle sequencing was used to detect variants in the coding and adjacent regions of the crystallin alpha A (CRYAA), crystallin beta B1 (CRYBB1), crystallin beta A4 (CRYBA4), crystallin gamma C (CRYGC), crystallin gamma D (CRYGD), and gap junction protein alpha 8 (GJA8) genes. RESULTS: Upon complete analysis of the 6 genes, three mutations in 2 genes were detected in 3 families, respectively. These mutations were not present in 96 normal controls. Of the three mutations, two novel heterozygous mutations in GJA8, c.136G>A (p.Gly46Arg) and c.116C>G (p.Thr39Arg), were found in two families with congenital cataract and microcornea. The rest one, a heterozygous c.34C>T (p.Arg12Cys) mutation in CRYAA, was identified in three patients from a family with nuclear cataract, microcornea with axial elongation. No mutation in the 6 genes was detected in the remaining 6 families. CONCLUSIONS: Mutations in GJA8 and CRYAA were identified in three families with cataract and microcornea. Elongation of axial length accompanied with myopia was a novel phenotype in the family with the c.34C>T mutation in CRYAA. Our results expand the spectrum of GJA8 mutations as well as their associated phenotypes.

SUBMITTER: Sun W

PROVIDER: S-EPMC3115747 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Mutational screening of six genes in Chinese patients with congenital cataract and microcornea.

Sun Wenmin W Xiao Xueshan X Li Shiqiang S Guo Xiangming X Zhang Qingjiong Q

Molecular vision 20110607

<h4>Purpose</h4>To identify mutations in 6 genes of 9 Chinese families with congenital cataract and microcornea.<h4>Methods</h4>Nine unrelated families with congenital cataract and microcornea were collected. Cycle sequencing was used to detect variants in the coding and adjacent regions of the crystallin alpha A (CRYAA), crystallin beta B1 (CRYBB1), crystallin beta A4 (CRYBA4), crystallin gamma C (CRYGC), crystallin gamma D (CRYGD), and gap junction protein alpha 8 (GJA8) genes.<h4>Results</h4> ...[more]

PMID: 21686328

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Project description:Purpose:To identify disease-causing gene mutations in 21 northern Chinese families with congenital cataracts. Methods:Medical record collection and ophthalmologic examinations were conducted for 21 families with congenital cataracts. A volume of 5 ml of peripheral blood was drawn from each participant for genomic DNA isolation. Thirty-four known candidate genes for congenital cataracts were analyzed in the probands of 21 families with targeted next-generation sequencing (NGS). Bioinformatics analysis of the sequence variants was performed through computational predictive programs. Sanger sequencing was used to perform the cosegregation analysis. Genotyping and haplotype analyses were performed in two patients with a p.V44M mutation in the GJA8 gene. Results:Twelve disease-causing mutations were detected in 13 of the 21 patients, and the mutation detection rate was 61.9%. The 12 gene mutations included one nonsense, one splice site, seven missense, and three insert and deletion (INDELs) mutations. Four mutations were novel. Of the 13 patients with pathogenic gene mutations, five (38.5%) were affected by mutations in lens crystallin genes, three (23%) were affected by mutations in connexin genes, three (23%) were affected by mutations in transcription factor genes, one (7.7%) was affected by a mutation in a transmembrane transporter gene, and one (7.7%) was affected by a mutation in a chromatin-modifying protein gene. Two families carried the p.V44M mutation in the GJA8 gene. Haplotype analysis revealed a chromosome region of 475 kb containing the mutation in the GJA8 gene was harbored by two families. Conclusions:Compared with traditional Sanger sequencing, targeted NGS for genetic testing of congenital cataracts markedly increases the mutation detection rate and is cost-effective. The p.V44M mutation in the GJA8 gene was the most common mutation and was due to a founder effect within the Chinese cohort studied. The results of this study expand the gene mutation spectrum of congenital cataracts.

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.

Dataset Information

Mutational screening of six genes in Chinese patients with congenital cataract and microcornea.

Publications

Mutational screening of six genes in Chinese patients with congenital cataract and microcornea.

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