Dataset Information

A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.

ABSTRACT: The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P?-8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency??A, p.G843E) of unknown significance. mRNA harboring c.2528?G?>?A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528?G?>?A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666?A?>?T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

SUBMITTER: Nishiguchi KM

PROVIDER: S-EPMC7846782 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.

Nishiguchi Koji M KM Miya Fuyuki F Mori Yuka Y Fujita Kosuke K Akiyama Masato M Kamatani Takashi T Koyanagi Yoshito Y Sato Kota K Takigawa Toru T Ueno Shinji S Tsugita Misato M Kunikata Hiroshi H Cisarova Katarina K Nishino Jo J Murakami Akira A Abe Toshiaki T Momozawa Yukihide Y Terasaki Hiroko H Wada Yuko Y Sonoda Koh-Hei KH Rivolta Carlo C Tsunoda Tatsuhiko T Tsujikawa Motokazu M Ikeda Yasuhiro Y Nakazawa Toru T

Communications biology 20210129 1

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10<sup>-8</sup>, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-syno ...[more]

PMID: 33514863

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Project description:ImportancePathogenic variants in retinitis pigmentosa GTPase regulator (RPGR) gene typically lead to a severe form of X-linked retinitis pigmentosa, which is associated with early severe vision loss.ObjectiveTo investigate an X-linked retinal degeneration family with atypical preservation of visual acuity in the presence of a novel deep intronic splice site RPGR c.779-5T>G variant.Design, setting, and participantsIn this case series, 3 members of an X-linked retinal degeneration family were studied by in-depth phenotyping and genetic screening at a single center. Data were collected and analyzed from November 2018 to March 2020.Main outcomes and measuresData were collected on full ophthalmic history, examination, and retinal imaging. A full retinitis pigmentosa gene panel was analyzed by next-generation sequencing. The pathogenicity of the RPGR c.779-5T>G variant was assessed by in silico splice prediction tools and by purpose-designed in vitro splicing assay.ResultsAn 84-year-old man was referred with clinical diagnosis of choroideremia and possible inclusion into a gene therapy trial. He presented with late-stage retinal degeneration and unusually preserved visual acuity (78 and 68 ETRDS letters) that clinically resembled choroideremia. His 23-year-old grandson was still in early stages of degeneration but showed a very different clinical picture, typical of retinitis pigmentosa. Next-generation sequencing identified a sole RPGR c.779-5T>G variant of undetermined pathogenicity in both cases. The daughter of the proband showed an RPGR carrier phenotype and was confirmed to carry the same variant. The molecular analysis confirmed that the RPGR c.779-5T>G variation reduced the efficiency of intron splicing compared with wild type, leading to a population of mutant and normal transcripts. The predicted consequences of the pathogenic variant are potential use of an alternative splice acceptor site or complete skipping of exon 8, resulting in truncated forms of the RPGR protein with different levels of glutamylation.Conclusions and relevanceThese results support the importance of careful interpretation of inconsistent clinical phenotypes between family members. Using a molecular splicing assay, a new pathogenic variant in a noncoding region of RPGR was associated with a proportion of normal and hypomorphic RPGR, where cones are likely to survive longer than expected, potentially accounting for the preserved visual acuity observed in this family.

Project description:BackgroundPanel-based targeted exome sequencing was applied to identify the pathogenic variants and genetic characteristics of retinitis pigmentosa (RP) in two Chinese families, and to gain a deeper understanding of the relationship between clinical manifestations and genotypes.MethodsA total of 17 subjects, comprising two probands (total patients: four subjects) and their family member, were recruited in this study. All subjects underwent comprehensive ophthalmic examinations and clinical evaluations, and the complete history and medical records were collected according to the standard procedures. All participants were screened using the multigene panel test (Target_Eye_792_V2 chip), and Sanger sequencing was used to confirm the candidate variants.ResultsAmong these two families, a total of three novel mutations in the EYS gene were identified in patients, including a homozygous frameshift mutation c.9252_9253insT detected in two patients in one family, and the compound heterozygous splicesite mutation c.5644+2T>C and frameshift mutation c.1920_1923delTGAG detected in two patients in the another family. All patients in both families had early onset of night blindness and poor visual acuity, and with typical posterior capsule opacification. The mutation co-segregated within all recruited individuals. In addition, one patient with compound heterozygous mutations was found to have typical blue-blindness symptoms and detected a previously reported disease-causing mutation c.235G>A in OPN1SW gene, which caused blue blindness manifestations and was first discovered in patient combined with RP causative genes.ConclusionsPanel-based targeted exome sequencing was used to identify three novel variants of RP causative gene, and we also detected a known pathogenic variants of blue-blindness causative genes in two patients. Our finding will provide a powerful basis for genetic counseling and enhance our current understanding of the genetics factors for RP families.

Dataset Information

A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.

Publications

A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa.

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