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      A novel intronic mutation of PDE6B is a major cause of autosomal recessive retinitis pigmentosa among Caucasus Jews

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          Abstract

          Purpose

          To identify the genetic basis for retinitis pigmentosa (RP) in a cohort of Jewish patients from Caucasia.

          Methods

          Patients underwent a detailed ophthalmic evaluation, including funduscopic examination, visual field testing, optical coherence tomography (OCT), and electrophysiological tests, electroretinography (ERG) and visual evoked potentials (VEP). Genetic analysis was performed with a combination of whole exome sequencing (WES) and Sanger sequencing. Bioinformatic analysis of the WES results was performed via a customized pipeline. Pathogenicity of the identified intronic variant was evaluated in silico using the web tool Human Splicing Finder, and in vitro, using a minigene-based splicing assay. Linkage disequilibrium (LD) analysis was used to demonstrate a founder effect, and the decay of LD over generations around the mutation in Caucasus Jewish chromosomes was modeled to estimate the age of the most recent common ancestor.

          Results

          In eight patients with RP from six unrelated families, all of Caucasus Jewish ancestry, we identified a novel homozygous intronic variant, located at position −9 of PDE6B intron 15. The c.1921–9C>G variant was predicted to generate a novel acceptor splice site, nine bases upstream of the original splice site of intron 15. In vitro splicing assay demonstrated that this novel acceptor splice site is used instead of the wild-type site, leading to an 8-bp insertion into exon 16, which is predicted to cause a frameshift. The presence of a common ancestral haplotype in mutation-bearing chromosomes was compatible with a founder effect.

          Conclusions

          The PDE6B c.1921–9C>G intronic mutation is a founder mutation that accounts for at least 40% (6/15 families) of autosomal recessive RP among Caucasus Jews. This result is highly important for molecular diagnosis, carrier screening, and genetic counseling in this population.

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          Most cited references30

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          Non-syndromic retinitis pigmentosa

          Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20-30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
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            Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.

            To devise a comprehensive multiplatform genetic testing strategy for inherited retinal disease and to describe its performance in 1000 consecutive families seen by a single clinician.
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              ISCEV guide to visual electrodiagnostic procedures

              Clinical electrophysiological testing of the visual system incorporates a range of noninvasive tests and provides an objective indication of function relating to different locations and cell types within the visual system. This document developed by the International Society for Clinical Electrophysiology of Vision provides an introduction to standard visual electrodiagnostic procedures in widespread use including the full-field electroretinogram (ERG), the pattern electroretinogram (pattern ERG or PERG), the multifocal electroretinogram (multifocal ERG or mfERG), the electrooculogram (EOG) and the cortical-derived visual evoked potential (VEP). The guideline outlines the basic principles of testing. Common clinical presentations and symptoms are described with illustrative examples and suggested investigation strategies.
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                Author and article information

                Journal
                Mol Vis
                Mol. Vis
                MV
                Molecular Vision
                Molecular Vision
                1090-0535
                2019
                22 February 2019
                : 25
                : 155-164
                Affiliations
                [1 ]Ruth & Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
                [2 ]Department of Ophthalmology, Bnai Zion Medical Center, Haifa, Israel
                [3 ]Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University of the Sacred Heart, Milan, Italy
                [4 ]Center for the Study of Rare Hereditary Diseases, Niguarda Ca' Granda Metropolitan Hospital, Milan, Italy
                [5 ]Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [6 ]Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                [7 ]Department of Ophthalmology, Hillel Yaffe Medical Center, Hadera, Israel
                [8 ]Alberto Moscona Department of Ophthalmology, Rambam Health Care Center, Haifa, Israel
                Author notes
                Correspondence to: Tamar Ben-Yosef, Rappaport Faculty of Medicine, Technion, P.O. Box 9649, Bat Galim, Haifa 31096, Israel; Phone: 972-4-829-5228; Fax: 972-4-829-5225; email: benyosef@ 123456technion.ac.il
                Article
                15 2018MOLVIS0296
                6386512
                30820151
                46175edd-7498-4baf-b2e9-6d99e05db40e
                Copyright © 2019 Molecular Vision.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited, used for non-commercial purposes, and is not altered or transformed.

                History
                : 14 October 2018
                : 20 February 2019
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                Vision sciences
                Vision sciences

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