Dataset Information

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort.

ABSTRACT: We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causing genes and seven inherited retinal disease (IRD)-causing genes, and the total mutation detection rate was 57%. The mutation detection rate was higher in patients who experienced visual deterioration at a younger age (75.4%, age of symptom onset under 10 years) and who had a family history of RP (70.7%). The most common causative genes were EYS (8.2%), USH2A (6.8%), and PDE6B (4.7%), but mutations were dispersed among the 51 RP/IRD genes generally. Meanwhile, the PDE6B mutation was the most common in patients experiencing initial symptoms in their first decade, EYS in their second to third decades, and USH2A in their fifth decades and older. Of note, WES revealed some unexpected genotypes: ABCC6, CHM, CYP4V2, RS1, TGFBI, VPS13B, and WDR19, which were verified by ophthalmological re-phenotyping.

SUBMITTER: Kim YJ

PROVIDER: S-EPMC8146864 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort.

Kim Yoon-Jeon YJ Kim You-Na YN Yoon Young-Hee YH Seo Eul-Ju EJ Seo Go-Hun GH Keum Changwon C Lee Beom-Hee BH Lee Joo-Yong JY

Genes 20210430 5

We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causin ...[more]

PMID: 33946315

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Project description:IntroductionRetinitis pigmentosa (RP) is a type of inherited retinal degeneration (IRD) that typically leads to vision loss in individuals of working age. Currently, over 100 genes and loci, as well as over 1000 individual variants, have been identified in relation to RP. The aim of this study was to investigate the genetic distribution and characteristics of Chinese patients with RP, as well as to describe and analyze the genetic features of the high-frequency variant from the RPGR gene.MethodsA total of 69 Chinese patients diagnosed with RP from 36 families were included in this study. Blood samples were collected, and DNA was extracted for genetic analysis. A custom panel targeting 822 genes associated with RP was designed for next-generation sequencing (NGS) analysis. The sequenced data were processed and analyzed using bioinformatics tools to identify genetic variants. Variant classification followed the guidelines provided by the American College of Medical Genetics and Genomics (ACMG), taking into consideration functional effects, population frequencies, and previous literature reports. Variant validation was performed using Sanger sequencing to confirm the presence of identified variants. The inheritance pattern of RP-associated variants was determined by analyzing the segregation pattern within families. Pedigrees were constructed based on the clinical and genetic information of the participants. Statistical analysis was conducted to summarize the clinical characteristics of the RP patients using descriptive statistics. Ethical considerations were strictly followed throughout the study, with approval obtained from the ethics committee and informed consent obtained from all participants.ResultsFollowing this, the identified variants were classified and subjected to statistical analysis. A total of 15 candidate genes associated with RP were identified, along with 39 variants, consisting of 36 reported variants and 3 novel variants. The majority of these variants were classified as pathogenic. The most common changes observed in this study were substitutions, followed by missense variants. Genetic analysis indicated that all variants occurred in the exon region. In the RPGR gene, half the variants are located in the ORF15. Gene, with half of variants located in ORF15. The most frequent variant within this group was RPGR NM_001034853.1: c.2236_2237del, which was identified in a large five-generation pedigree. The three novel variants reported in this study include NM_015629.3: c.1168_1169insGATTCAGCCTGGCC of PRPF31, NM_001034853.1: c.3026_3027insAGAGGGAGAGGAAGAAGG and NM_000328.2: c.611T>G of RPGR.ConclusionsThe findings of this study offer valuable insights into the genetic variants responsible for RP in affected individuals, which can be utilized for genetic counseling and diagnosis. This underscores the significance of genetic testing in the management and treatment of RP.

Project description:PurposeRetinitis pigmentosa (RP) shows great diversity between genotypes and phenotypes, and it is important to identify the causative genes. This study aimed to analyze the molecular profiles, associated ocular characteristics, and progression of RP in Korean patients.MethodsAll the genetic variants in patients with RP, identified using targeted next-generation sequencing (NGS) with a panel of 88 RP-related genes between November 2018 and November 2019, were retrospectively reviewed. All the patients underwent comprehensive ophthalmological evaluations, and their clinical and family histories were recorded. The best-corrected visual acuity (BCVA) deterioration and photoreceptor disruption progression rates were determined based on the major causative mutational genes using nonlinear mixed models, and the differences among them were investigated using the interaction effect.ResultsAmong the 144 probands, 82 variants in 24 causative genes were identified in 77 families (53.5%). Most of the RP cases were associated with autosomal recessive variants (N = 64 (44.4%)), followed by autosomal dominant (N = 10 (6.9%)) and X-linked variants (N = 3 (2.1%)). The four most frequently affected genes were EYS (N = 15 (10.4%)), USH2A (N = 12 (8.3%)), PDE6B (N = 9 (6.3%)), and RP1 (N = 8 (5.6%)). Epiretinal membranes and cystoid macular edema were frequently noted in the patients with USH2A (75.0%) and PDE6B (50.0%) variants, respectively. During the follow-up period, the BCVA and photoreceptor disruption changes were significantly different among the patients carrying the four common causative genes (P=0.014 and 0.034, resp.). Patients with PDE6B variants showed faster BCVA changes (0.2 LogMAR/10 years), and those with USH2A variants showed the fastest ellipsoid zone disruptions (-170.4 µm/year).ConclusionIn conclusion, our genetic analysis using targeted NGS provides information about the prevalence of RP-associated mutations in Korean patients. Delineating clinical characteristics according to genetic variations may help clinicians identify subtype features and predict the clinical course of RP.

Dataset Information

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort.

Publications

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort.

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