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      NGS-based Molecular diagnosis of 105 eyeGENE ® probands with Retinitis Pigmentosa

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          Abstract

          The National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE ®) was established in an effort to facilitate basic and clinical research of human inherited eye disease. In order to provide high quality genetic testing to eyeGENE ®’s enrolled patients which potentially aids clinical diagnosis and disease treatment, we carried out a pilot study and performed Next-generation sequencing (NGS) based molecular diagnosis for 105 Retinitis Pigmentosa (RP) patients randomly selected from the network. A custom capture panel was designed, which incorporated 195 known retinal disease genes, including 61 known RP genes. As a result, disease-causing mutations were identified in 52 out of 105 probands (solving rate of 49.5%). A total of 82 mutations were identified, and 48 of them were novel. Interestingly, for three probands the molecular diagnosis was inconsistent with the initial clinical diagnosis, while for five probands the molecular information suggested a different inheritance model other than that assigned by the physician. In conclusion, our study demonstrated that NGS target sequencing is efficient and sufficiently precise for molecular diagnosis of a highly heterogeneous patient cohort from eyeGENE ®.

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          Perspective on genes and mutations causing retinitis pigmentosa.

          Exceptional progress has been made during the past two decades in identifying genes causing inherited retinal diseases such as retinitis pigmentosa. An inescapable consequence is that the relationship between genes, mutations, and clinical findings has become very complex. Success in identifying the causes of inherited retinal diseases has many implications, including a better understanding of the biological basis of vision and insights into the processes involved in retinal pathology. From a clinical point of view, there are two important questions arising from these developments: where do we stand today in finding disease-causing mutations in affected individuals, and what are the implications of this information for clinical practice? This perspective addresses these questions specifically for retinitis pigmentosa, but the observations apply generally to other forms of inherited eye disease.
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            Next-generation genetic testing for retinitis pigmentosa

            Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling.
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              Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.

              Usher syndrome type IIa (OMIM 276901), an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, maps to the long arm of human chromosome 1q41 between markers AFM268ZD1 and AFM144XF2. Three biologically important mutations in Usher syndrome type IIa patients were identified in a gene (USH2A) isolated from this critical region. The USH2A gene encodes a protein with a predicted size of 171.5 kilodaltons that has laminin epidermal growth factor and fibronectin type III motifs; these motifs are most commonly observed in proteins comprising components of the basal lamina and extracellular matrixes and in cell adhesion molecules.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                15 December 2015
                2015
                : 5
                : 18287
                Affiliations
                [1 ]Human Genome Sequencing Center, Baylor College of Medicine , Houston, Texas, USA
                [2 ]Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas, USA
                [3 ]Ophthalmic Genetics and Visual Function Branch, National Eye Institute/National Institutes of Health , Bethesda, Maryland, USA
                [4 ]Wilmer Eye Institute, Johns Hopkins University , Baltimore, Maryland, USA
                [5 ]Program in Developmental Biology, Baylor College of Medicine , Houston, Texas, USA
                [6 ]The Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, Baylor College of Medicine , Houston, Texas, USA
                [7 ]Structural and Computational Biology and molecular Biophysics Graduate Program, Baylor College of Medicine , Houston, Texas, USA
                Author notes
                Article
                srep18287
                10.1038/srep18287
                4678898
                26667666
                8c449cff-513f-4611-b1dd-fa3d8444f910
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 21 August 2015
                : 10 November 2015
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