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Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.

ABSTRACT: Due to the genotype-phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype-phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G?>?A, c.1488del, c.1547T?>?C, c.1604T?>?A, c.1669C?>?T, c.1712C?>?T, c.2395C?>?T, c.2492C?>?T, c.592G?>?A, and c.815G?>?A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C?>?T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B-RP.

SUBMITTER: Kim YN

PROVIDER: S-EPMC7658990 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.

Kim You Na YN Song Joon Seon JS Oh Seak Hee SH Kim Yoon Jeon YJ Yoon Young Hee YH Seo Eul-Ju EJ Seol Chang Ahn CA Lee Sae-Mi SM Choi Jong-Moon JM Seo Go Hun GH Keum Changwon C Lee Beom Hee BH Lee Joo Yong JY

Scientific reports 20201111 1

Due to the genotype-phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype-phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median ...[more]

PMID: 33177553

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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.

Project description:Purpose: To investigate the clinical features, natural course, and genetic characteristics of Koreans with rhodopsin-associated retinitis pigmentosa (RHO-associated RP). Design: We conducted a retrospective, multicenter, observational cohort study. Participants: We reviewed the medical records of 42 patients with RHO-associated RP of 36 families who visited 4 hospitals in Korea. Methods: Patients with molecular confirmation of pathogenic variants of the RHO gene were included. The patients were divided into two subgroups: the generalized and sector RP groups. A central visual field of the better-seeing eye of <10° or a best-corrected visual acuity of the better-seeing eye <20/40 indicated the progression to late-stage RP. Results: The mean age at which symptoms first appeared was 26.3 ± 17.9 years (range: 8-78 years), and the mean follow-up period was 80.9 ± 68.7 months (range: 6-268 months). At the last follow-up visit, the generalized RP group showed a significantly higher rate of visual field impairment progression to late-stage RP than that of the sector RP group (22 of 35 [62.9%] vs. 0 of 7 [0.0%], p = 0.003). No cases in the sector RP group progressed to generalized RP. Best-corrected visual acuity deterioration to late-stage RP was observed only in the generalized RP group (13 of 35 patients; 37.1%), whereas no deterioration was observed in the sector RP group. We identified 16 known and three novel RHO mutations, including two missense mutations (p.T108P and p.G121R) and one deletion mutation (p.P347_A348del). The pathogenic variants were most frequently detected in exon 1 (14 of 36 [38.9%]). The most common pathogenic variants were p.P347L and T17M (5 of 36 [13.9%] families). Among 42 patients of 36 families, 35 patients of 29 families (80.6%) presented with the generalized RP phenotype, and seven patients of seven families (19.4%) presented with the sector RP phenotype. Three variants (p.T17M, p.G101E, and p.E181K) presented with both the generalized and sector RP phenotypes. Conclusion: This multicenter cohort study provided information on the clinical and genetic features of RHO-associated RP in Koreans. It is clinically important to expand the genetic spectrum and understand genotype-phenotype correlations to ultimately facilitate the development of gene therapy.

Project description:PURPOSE: Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. METHODS: The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. RESULTS: THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. CONCLUSIONS: This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

Dataset Information

Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.

Publications

Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.

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