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


          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.


          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.


          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 references 30

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          Non-syndromic retinitis pigmentosa

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            Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci.

            In spite of recent advances in identifying genes causing monogenic human disease, very little is known about the genes involved in polygenic disease. Three families were identified with mutations in the unlinked photoreceptor-specific genes ROM1 and peripherin/RDS, in which only double heterozygotes develop retinitis pigmentosa (RP). These findings indicate that the allelic and nonallelic heterogeneity known to be a feature of monogenic RP is complicated further by interactions between unlinked mutations causing digenic RP. Recognition of the inheritance pattern exemplified by these three families might facilitate the identification of other examples of digenic inheritance in human disease.
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              A simple and efficient non-organic procedure for the isolation of genomic DNA from blood.


                Author and article information

                Mol Vis
                Mol. Vis
                Molecular Vision
                Molecular Vision
                22 February 2019
                : 25
                : 155-164
                [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
                15 2018MOLVIS0296
                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.

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