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Molecular and structural analysis of genetic variations in congenital cataract.

ABSTRACT: OBJECTIVE: To determine the relative contributions of mutations in congenital cataract cases in an Indian population by systematic screening of genes associated with cataract. METHODS: We enrolled 100 congenital cataract cases presenting at the Dr. R. P. Centre for Ophthalmic Sciences, a tertiary research and referral hospital (AIIMS, New Delhi, India). Crystallin, alpha A (CRYAA), CRYAB, CRYGs, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, beaded filament structural protein 1 (BFSP1), gap function protein, alpha 3 (GJA3), GJA8, and heat shock transcription factor 4 gene genes were amplified. Protein structure differences analysis was performed using Discovery Studio (DS) 2.0. RESULTS: The mean age of the patients was 17.45±16.51 months, and the age of onset was 1.618±0.7181 months. Sequencing analysis of 14 genes identified 18 nucleotide variations. Fourteen variations were found in the crystallin genes, one in Cx-46 (GJA3), and three in BFSP1. CONCLUSIONS: Congenital cataract shows marked clinical and genetic heterogeneity. Five nucleotide variations (CRYBA4:p.Y67N, CRYBB1:p.D85N, CRYBB1:p.E75K, CRYBB1:p.E155K, and GJA3:p.M1V) were predicted to be pathogenic. Variants in other genes might also be involved in maintaining lens development, growth, and transparency. The study confirms that the crystallin beta cluster on chromosome 22, Cx-46, and BFSP1 plays a major role in maintaining lens transparency. This study also expands the mutation spectrum of the genes associated with congenital cataract.

SUBMITTER: Kumar M

PROVIDER: S-EPMC3850972 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Molecular and structural analysis of genetic variations in congenital cataract.

Kumar Manoj M Agarwal Tushar T Kaur Punit P Kumar Manoj M Khokhar Sudarshan S Dada Rima R

Molecular vision 20131124

<h4>Objective</h4>To determine the relative contributions of mutations in congenital cataract cases in an Indian population by systematic screening of genes associated with cataract.<h4>Methods</h4>We enrolled 100 congenital cataract cases presenting at the Dr. R. P. Centre for Ophthalmic Sciences, a tertiary research and referral hospital (AIIMS, New Delhi, India). Crystallin, alpha A (CRYAA), CRYAB, CRYGs, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, beaded filament structural protein 1 (BFSP1), ga ...[more]

PMID: 24319337

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Project description:ImportanceIdentification of geographic population-based differences in genotype and phenotype heterogeneity are important for targeted and patient-specific diagnosis and treatment, counseling, and screening strategies.ObjectiveTo report disease-causing variants and their detailed phenotype in patients with bilateral congenital cataract from a single center in Switzerland and thereby draw a genetic map and perform a genotype-phenotype comparison of this cohort.Design, setting, and participantsThis clinical and molecular-genetic cohort study took place through the collaboration of the Department of Ophthalmology at the University Hospital Zurich and the Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland. Thirty-seven patients from 25 families with different types of bilateral congenital cataract were included. All participating family members received a comprehensive eye examination. Whole exome sequencing was performed in the index patients, followed by a filtering process to detect possible disease-associated variants in genes previously described in association with congenital cataract. Probable disease-causing variants were confirmed by Sanger sequencing in available family members. All data were collected from January 2018 to June 2020, and the molecular-genetic analyses were performed from January 2019 to July 2020.Main outcomes and measuresIdentification of the underlying genetic causes of bilateral congenital cataract, including novel disease-causing variants and phenotype correlation.ResultsAmong the 37 patients (18 [49%] male and 19 [51%] female; mean [SD] age, 17.3 [15.9] years) from 25 families, pathogenic variants were detected in 20 families (80% detection rate), which included 13 novel variants in the following genes: BCOR, COL4A1, CRYBA2, CRYBB2, CRYGC, CRYGS, GJA3, MAF, NHS, and WFS1. Putative disease-causing variants were identified in 14 of 20 families (70%) as isolated cases and in 6 of 20 families (30%) with syndromic cases. A recessive variant in the CRYBB2 gene in a consanguineous family with 2 affected siblings showing a nuclear and sutural cataract was reported in contrast to previously published reports. In addition, the effect on splicing in a minigene assay of a novel splice site variant in the NHS gene (c.[719-2A>G]) supported the pathogenicity of this variant.Conclusions and relevanceThis study emphasizes the importance of genetic testing of congenital cataracts. Known dominant genes need to be considered for recessive inheritance patterns. Syndromic types of cataract may be underdiagnosed in patients with mild systemic features.

Project description:BackgroundCongenital cataract (CC) and congenital heart disease (CHD) are significant birth defects. In clinical practice, the concurrence of CC and CHD is frequently observed in patients. Additionally, some monogenic diseases, copy number variation (CNV) syndromes, and diseases associated with intrauterine infection involve both cataract and heart defects. However, little is known about the association between CC and CHD. Here, we characterised the demographic, clinical, and genetic features of patients with CC and heart defects.MethodsMedical records for 334 hospitalised patients diagnosed with CC were reviewed. Demographic and clinical features of patients with CC with and without CHD were compared. Clinical and genomic information for patients with 'cataract' and 'cardiac defects' were reviewed from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). Microarray-based comparative genomic hybridisation and whole-exome sequencing were performed in 10 trio families with CC and CHD to detect de novo genomic alterations, including copy number variants and single nucleotide changes.ResultsIn a retrospective analysis of 334 patients with CC over the past 10 years at our hospital, we observed a high proportion of patients (41.13%) with CHD (including innocent CHD, which reported as left-to-right shunt in echocardiography test). The CC with CHD group had higher incidences of preterm birth and Down's syndrome than the CC without CHD group. Atrial septal defect was the most frequent heart defect. A total of 44 cases with cataracts and heart diseases were retrieved from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). In total, 52 genomic alterations were reported, 44% of which were de novo germline variants. In the 10 trio families with CC and CHD, we found de novo CNVs responsible for two well-known chromosomal disorders and identified a novel pathogenic mutation in GJA8 responsible for CC.ConclusionsWe observed significant associations between CHD and CC in our 10-year patient cohort. Based on the cohort and data from DECIPHER, developmental syndromes in some patients were due to genetic defects, thus explaining the concurrence of CC and CHD. Additionally, we detected de novo mutations as an independent cause of cataracts. Our findings suggest that developmental syndromes in patients with CC deserve more attention in clinical practice by ophthalmologists.

Project description:ImportanceThe p.Asp67Tyr genetic variant in the GJA3 gene is responsible for congenital cataracts in a family with a high incidence of glaucoma following cataract surgery.ObjectiveTo describe the clinical features of a family with a strong association between congenital cataracts and glaucoma following cataract surgery secondary to a genetic variant in the GJA3 gene (NM_021954.4:c.199G>T, p.Asp67Tyr).Design, setting, and participantsThis was a retrospective, observational, case series, genetic association study from the University of Iowa spanning 61 years. Examined were the ophthalmic records from 1961 through 2022 of the family members of a 4-generation pedigree with autosomal dominant congenital cataracts.Main outcomes and measuresFrequency of glaucoma following cataract surgery and postoperative complications among family members with congenital cataract due to the p.Asp67Tyr GJA3 genetic variant.ResultsMedical records were available from 11 of 12 family members (7 male [63.6%]) with congenital cataract with a mean (SD) follow-up of 30 (21.7) years (range, 0.2-61 years). Eight of 9 patients with congenital cataracts developed glaucoma, and 8 of 8 patients who had cataract surgery at age 2 years or younger developed glaucoma following cataract surgery. The only family member with congenital cataracts who did not develop glaucoma had delayed cataract surgery until 12 and 21 years of age. Five of 11 family members (45.5%) had retinal detachments after cataract extraction and vitrectomy. No patients developed retinal detachments after prophylactic 360-degree endolaser.Conclusions and relevanceThe GJA3 genetic variant, p.Asp67Tyr, was identified in a 4-generation congenital cataract pedigree from Iowa. This report suggests that patients with congenital cataract due to some GJA3 genetic variants may be at especially high risk for glaucoma following cataract surgery. Retinal detachments after cataract extraction in the first 2 years of life were also common in this family, and prophylactic retinal endolaser may be indicated at the time of surgery.

Project description:PURPOSE: Age-related cataract (ARC) is a complex multifactorial disorder, including genetic and environmental factors. Ezrin (EZR), a member of the ezrin/radixin/moesin (ERM) protein family, plays a crucial role in the development of the lens as a plasma membrane-cytoskeleton linker. We conducted this study to investigate the role of genetic variations of ezrin and the relationship between single nucleotide polymorphisms (SNPs) in EZR and susceptibility to ARC in a Chinese population. METHODS: A total of 205 sporadic age-related cataract patients and 218 unrelated random healthy controls participated in our study. Genomic DNA was extracted from peripheral blood leukocytes. All exons of EZR were sequenced after being amplified with polymerase chain reaction. The functional consequences of the mutations were analyzed using PolyPhen2. SNP statistical analysis was performed using SNPstats. RESULTS: We found three novel variations in 205 patients. None presented in the 218 controls, including c.441C>G, c.924G>C, and c.1503G>A. PolyPhen2 predicted that the c.924G>C mutation probably had pathogenicity. Compared with the healthy controls, the rs5881286 -/GT genotype and - allele frequencies (p=0.0012; odds ratio [OR]=3.37; 95% confidence interval [CI]=1.70-6.70; p=3.96e-5; ?(2)=18.98, respectively), rs2242318 T/C genotype and C allele frequencies (p=0.0045; OR=3.40; 95% CI=1.70-6.79; p=8.82e-6; ?(2)=21.86, respectively), and rs144581330 A/G genotype and G allele frequencies (p=0.0472; OR=14.46; 95% CI=1.29-162.43; p=0.0244, ?(2)=6.99, respectively) were higher in the patients with age-related cataract. SNP rs144581330 in exon 2 was also predicted to be probably damaging by PolyPhen2. Haplotype association including the - allele of rs5881286, C allele of rs2242318, and A allele of rs144581330 exhibited significantly higher distribution in the patients with ARC (p=8.0e-4; OR=3.38; 95% CI=1.66-6.87). CONCLUSIONS: This study suggests that the genetic variations and SNPs in the gene EZR possibly contribute to the development of age-related cataracts in the Chinese population.

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Molecular and structural analysis of genetic variations in congenital cataract.

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Molecular and structural analysis of genetic variations in congenital cataract.

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