Mutation Analysis of Seven Known Glaucoma-Associated Genes in Chinese Patients With Glaucoma

Huang, Xiaobo; Wen, Feng; Guo, Xiangming; Li, Shiqiang; Xiao, Xueshan; Jia, Xiaoyun; Xing, Liu; Zhang, Qingjiong

doi:10.1167/iovs.14-13927

Cited by 51 publications

(58 citation statements)

References 48 publications

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“…32 However, a WES study failed to detect any deleterious LTBP2 variants in Chinese POAG, JOAG, and PCG patients. 57 The prevalence of LTBP2-predicted pathogenic variants in our Australian cohort (2.8%) was lower than the rate reported in the Iranian population. Taken with the evidence from the Chinese study, the prevalence rate of LTBP2 in POAG appears to be heavily dependent on ethnicity, just like the prevalence rate of CYP1B1.…”

contrasting

confidence: 67%

“…40,61 In a Chinese WES study, the prevalence of WDR36 variants was high and similar to MYOC; however, no controls were sequenced. 57 Our study found that WDR36 variants were the second most frequent after MYOC, although by a large margin. However, it is highly unlikely that WDR36 variants are causative for POAG in our cohort of advanced glaucoma participants given the higher prevalence of WDR36 variants in our age-matched local controls and AOGC controls than in POAG cases.…”

Section: 57mentioning

confidence: 55%

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Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Zhou

Souzeau

Siggs

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Zhou T, Souzeau E, Siggs OM, et al. Contribution of mutations in known Mendelian glaucoma genes to advanced early-onset primary openangle glaucoma. Invest Ophthalmol Vis Sci. 2017;58:153758: -154458: . DOI: 10.1167 PURPOSE. Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. METHODS.The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes.RESULTS. Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] ¼ 16.62, P ¼ 6.31310 À16 ).CONCLUSIONS. Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

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contrasting

confidence: 67%

Section: 57mentioning

confidence: 55%

Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Zhou

Souzeau

Siggs

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…9 The variants detected in proband III:4 were filtered using the following steps: (1) variations predicted to affect the coding residues or mRNA splicing were selected; (2) after comparison with the 1000 Genomes Project database, variants with a minor allele frequency (MAF) o0.01 were selected; (3) variants in genes associated with ocular diseases were selected; (4) the remaining variants were compared with ethnicity-matched regional controls (195 patients with high myopia and 310 patients with hereditary retinal diseases but not glaucoma based on our unpublished data of whole exome sequencing on patients with hereditary eye diseases) to exclude ethnicity-specific polymorphisms (MAF ≥ 0.01); (5) effects of the remaining variants on coding residues of the remaining variants were analyzed using Polyphen-2 and SIFT; 15,16 (6) the remaining variants predicted to have damaging effects on coding sequence and to affect splicing were confirmed by Sanger sequencing and validated in family members, as well as in 192 normal controls. A pair of primers used to confirm the novel variant in GJA1 were designed using the Primer3 online tool (http://frodo.wi.mit.edu/primer3/): 17 GJA1-Forward 5′-aaaagagatccctgcccaca-3′ and GJA1-Reverse 5′-aggctgttgagtaccacctc-3′.…”

Section: Methodsmentioning

confidence: 99%

“…The polymerase chain reaction was used to amplify the target variants, and the amplicons were analyzed with an ABI BigDye Terminator cycle sequencing kit v3.1 (Applied Biosystems, Foster City, CA, USA) on an ABI3130 Genetic Analyzer (Applied Biosystems) as described in a previous study. 9 …”

Section: Methodsmentioning

confidence: 99%

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A novel truncation mutation in GJA1 associated with open angle glaucoma and microcornea in a large Chinese family

Huang

Wang

Xiao

et al. 2015

Eye

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Purpose To identify genetic defects in a large family with open angle glaucoma (OAG) and microcornea. Methods Genomic DNA was prepared from leukocytes of 15 individuals from three generations of a Chinese family, including seven individuals with OAG and microcornea, one with microcornea alone, and seven healthy individuals. Whole exome sequencing was performed on genomic DNA of the proband. Candidate variants were obtained through multiple steps of bioinformatics analysis and validated by Sanger sequencing and segregation analysis. Results Exome sequencing detected a candidate variant in GJA1, a novel truncation mutation (c.791_792delAA, p.K264Ifs*43). This mutation was present in all seven individuals with OAG and microcornea and the individual with microcornea alone, but not in the seven unaffected relatives in the family. It was not present in 1394 alleles from 505 unrelated controls without glaucoma and 192 normal controls. Extraocular signs were not observed in seven out of the eight individuals; only one was affected with dental enamel hypoplasia and syndactyly. Conclusions A novel truncation mutation in GJA1 is associated with OAG and microcornea in a Chinese family. This suggests that GJA1 should be included as a candidate gene for glaucoma.

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Genetic Associations of Primary Angle-Closure Disease

Liang,

Wang,

Rong

et al. 2024

JAMA Ophthalmol

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ImportanceEffects of genetic variants on primary angle-closure disease remained uncertain.ObjectiveTo systematically review the associations of common single-nucleotide variants (SNVs) and rare coding variants with primary angle-closure disease, its subtypes (including primary angle-closure glaucoma, primary angle-closure suspect, and primary angle-closure) and progression.Data SourcesEligible studies from PubMed, Embase, and Web of Science were retrieved up to April 3, 2023. SNV information was extracted from eligible reports and 2 genome-wide association studies summary statistics, UK BioBank and FinnGen.Study SelectionStudies providing analyzable genotype or allele data in a case-control design for primary angle-closure disease association and longitudinal case-only design for primary angle-closure disease progression.Data Extraction and SynthesisPRISMA guidelines were used for literature screening and the Newcastle Ottawa Scale for data quality assessment. Pooled effect size with 95% CIs of SNV associations were calculated using fixed- or random-effect models according to I2 statistics.Main Outcomes and MeasuresSNVs reported in 2 or more studies were meta-analyzed to generate pooled odds ratios and P values. Common and rare coding variants from single reports were summarized.ResultsSixty-nine citations were eligible for meta-analysis on overall primary angle-closure disease, involving 206 SNVs in 64 genes or loci. Seventeen SNVs in 15 genes or loci showed associations with primary angle-closure disease, and 15 SNVs in 13 genes or loci showed associations with primary angle-closure glaucoma. Two SNVs, ABCA1 rs2422493 and ZNRF3 rs3178915, were associated only with primary angle-closure disease. Two SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect, and 1 SNV, MMP9 rs3918249, was associated with primary angle-closure. This systematic review and meta-analysis newly confirmed 7 genes or loci associated with primary angle-closure glaucoma: ATOH7, CALCRL, FBN1, IL6, LOXL1, MMP19, and VAV3. Common and rare coding variants in 16 genes or loci that have been associated with primary angle-closure disease were cataloged. Stratification analysis revealed different primary angle-closure disease–associated genes in different ethnic populations. Only 1 study regarding the genetic association of primary angle-closure glaucoma progression was identified.Conclusions and RelevanceThis study revealed the genetic complexity of primary angle-closure disease, involving common SNVs and rare coding variants in more than 30 genes or loci, with ethnic and phenotypic diversities. Further replication, genotype-phenotype correlation, and pathway analyses are warranted.

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Mutation Analysis of Seven Known Glaucoma-Associated Genes in Chinese Patients With Glaucoma

Cited by 51 publications

References 48 publications

Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

A novel truncation mutation in GJA1 associated with open angle glaucoma and microcornea in a large Chinese family

Genetic Associations of Primary Angle-Closure Disease

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