Dataset Information

Exome sequencing in families with chronic central serous chorioretinopathy.

ABSTRACT: BACKGROUND:Central serous chorioretinopathy (CSC) is a chorioretinal disease characterized by fluid accumulation between the neuroretina and retinal pigment epithelium with unknown etiology. Family studies have suggested a heritable component for CSC with an autosomal dominant inheritance pattern. Therefore, exome sequencing was performed on familial cCSC to indentify the genetic components contributing to familial cCSC. METHODS:Exome sequencing was performed on 72 individuals of 18 families with CSC. In these families, we determined whether rare genetic variants (minor allele frequency < 1%) were segregated with CSC and also performed familial gene-burden analysis. RESULTS:In total, 11 variants segregated in two out of 18 families. One of these variants, c.4145C>T; p.T1382I (rs61758735) in the PTPRB gene, was also associated with CSC in a large case-control cohort sequenced previously (p = 0.009). Additionally, in 28 genes two or more different heterozygous variants segregated in two or more families, but no gene showed consistent associations in both the family gene-burden results and gene-burden analysis in the case-control cohort. CONCLUSION:We identified potential candidate genes for familial CSC and managed to exclude Mendelian inheritance of variants in one or a limited number of genes. Instead, familial CSC may be a heterogeneous Mendelian disease caused by variants in many different genes, or alternatively CSC may represent a complex disease to which both environmental factors and genetics contribute.

SUBMITTER: Schellevis RL

PROVIDER: S-EPMC6465660 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Exome sequencing in families with chronic central serous chorioretinopathy.

Schellevis Rosa L RL van Dijk Elon H C EHC Breukink Myrte B MB Keunen Jan E E JEE Santen Gijs W E GWE Hoyng Carel B CB de Jong Eiko K EK Boon Camiel J F CJF den Hollander Anneke I AI

Molecular genetics & genomic medicine 20190206 4

<h4>Background</h4>Central serous chorioretinopathy (CSC) is a chorioretinal disease characterized by fluid accumulation between the neuroretina and retinal pigment epithelium with unknown etiology. Family studies have suggested a heritable component for CSC with an autosomal dominant inheritance pattern. Therefore, exome sequencing was performed on familial cCSC to indentify the genetic components contributing to familial cCSC.<h4>Methods</h4>Exome sequencing was performed on 72 individuals of ...[more]

PMID: 30724488

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Project description:Chronic central serous chorioretinopathy (cCSC) is a multifactorial eye disease characterized by subretinal fluid accumulation that leads to vision loss. Clinically, cCSC is associated with stress, hypercortisolism and corticosteroid use, and is more frequent in males (80%) than in females (20%). Current genetic studies on cCSC have thus far focussed on common variants, but familial occurrence of cCSC also suggests a role for rare variants in the disease susceptibility. Therefore, in this study, we performed exome sequencing of cCSC patients to elucidate the role of rare (protein-altering) variants in the disease. Exome sequencing was performed on 269 cCSC patients and 1,586 controls. Data were processed according to the Genome-Analysis-Toolkit (GATK) best practices. Principal component analysis was performed to check for genetic ancestry and only unrelated subjects of European descent were retained. Burden, SKAT and SKAT-O tests were performed using 2 different grouping criteria. One group included protein-altering variants only, while the other contained synonymous and splice site variants as well. The gene-based analyses were performed using the SKAT R-package correcting for two principal components using two approaches; (1) on the entire cohort correcting for sex and (2) on males and females separately. Additionally, the gene-based associations of genes at previously reported cCSC loci were investigated. After filtering, the dataset contained 263 cCSC patients (208 males [79%]) and 1352 controls (671 males [50%]) carrying 197,915 protein-altering variants in 16,370 genes and 330,689 exonic variants in 18,173 genes. Analysis stratified by sex identified significant associations with the PIGZ (PSKAT?=?9.19?×?10-7 & PSKAT-O?=?2.48?×?10-6), DUOX1 (PSKAT?=?1.03?×?10-6), RSAD1 (PSKAT?=?1.92?×?10-7 & PSKAT-O?=?8.57?×?10-8) and LAMB3 (PBurden?=?1.40?×?10-6 & PSKAT-O?=?1.14?×?10-6) genes in female cCSC patients, after correction for multiple testing. The number of rare variant carriers in these genes was significantly higher in the female cCSC cohort compared to female controls (45,5% vs. 18.5%, P?=?1.92?×?10-6, OR?=?3.67 [95% CI?=?2.09-6.46]). No significant associations were identified in the entire cohort nor in the male patients. In this exome study on cCSC patients, we have identified PIGZ, DUOX1, RSAD1 and LAMB3 as potential new candidate genes for cCSC in females. The sex-specific associations identified here suggest a possible interaction between rare genetic factors and sex for cCSC, but replication of these findings in additional cohorts of cCSC patients is necessary.

Dataset Information

Exome sequencing in families with chronic central serous chorioretinopathy.

Publications

Exome sequencing in families with chronic central serous chorioretinopathy.

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