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      Toward an elucidation of the molecular genetics of inherited retinal degenerations

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          While individually classed as rare diseases, hereditary retinal degenerations (IRDs) are the major cause of registered visual handicap in the developed world. Given their hereditary nature, some degree of intergenic heterogeneity was expected, with genes segregating in autosomal dominant, recessive, X-linked recessive, and more rarely in digenic or mitochondrial modes. Today, it is recognized that IRDs, as a group, represent one of the most genetically diverse of hereditary conditions - at least 260 genes having been implicated, with 70 genes identified in the most common IRD, retinitis pigmentosa (RP). However, targeted sequencing studies of exons from known IRD genes have resulted in the identification of candidate mutations in only approximately 60% of IRD cases. Given recent advances in the development of gene-based medicines, characterization of IRD patient cohorts for known IRD genes and elucidation of the molecular pathologies of disease in those remaining unresolved cases has become an endeavor of the highest priority. Here, we provide an outline of progress in this area.

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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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            Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.

            Next-generation sequencing-based methods are being adopted broadly for genetic diagnostic testing, but the performance characteristics of these techniques with regard to test accuracy and reproducibility have not been fully defined. We developed a targeted enrichment and next-generation sequencing approach for genetic diagnostic testing of patients with inherited eye disorders, including inherited retinal degenerations, optic atrophy, and glaucoma. In preparation for providing this genetic eye disease (GEDi) test on a CLIA-certified basis, we performed experiments to measure the sensitivity, specificity, and reproducibility, as well as the clinical sensitivity, of the test. The GEDi test is highly reproducible and accurate, with sensitivity and specificity of 97.9 and 100%, respectively, for single-nucleotide variant detection. The sensitivity for variant detection was notably better than the 88.3% achieved by whole-exome sequencing using the same metrics, because of better coverage of targeted genes in the GEDi test as compared with a commercially available exome capture set. Prospective testing of 192 patients with inherited retinal degenerations indicated that the clinical sensitivity of the GEDi test is high, with a diagnostic rate of 51%. Based on quantified performance metrics, the data suggest that selective targeted enrichment is preferable to whole-exome sequencing for genetic diagnostic testing.
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              Emerging therapies for inherited retinal degeneration.

              Inherited retinal degenerative diseases, a genetically and phenotypically heterogeneous group of disorders, affect the function of photoreceptor cells and are among the leading causes of blindness. Recent advances in molecular genetics and cell biology are elucidating the pathophysiological mechanisms underlying these disorders and are helping to identify new therapeutic approaches, such as gene therapy, stem cell therapy, and optogenetics. Several of these approaches have entered the clinical phase of development. Artificial replacement of dying photoreceptor cells using retinal prostheses has received regulatory approval. Precise retinal imaging and testing of visual function are facilitating more efficient clinical trial design. In individual patients, disease stage will determine whether the therapeutic strategy should comprise photoreceptor cell rescue to delay or arrest vision loss or retinal replacement for vision restoration.

                Author and article information

                Hum Mol Genet
                Hum. Mol. Genet
                Human Molecular Genetics
                Oxford University Press
                01 August 2017
                16 May 2017
                16 May 2017
                : 26
                : R1 , Special Review Issue: Eye-Related Disorders
                : R2-R11
                [1 ]Institute of Genetics, School of Genetics and Microbiology, University of Dublin, Trinity College, Dublin 2, Ireland
                [2 ]Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland
                Author notes
                [* ]To whom correspondence should be addressed at: The Ocular Genetics Unit, Institute of Genetics, Trinity College, University of Dublin, Dublin 2, Ireland. Tel: +353 18962482; Email: gjfarrar@ 123456tcd.ie (G.J.F.); Email: pete.humphries@ 123456tcd.ie (P.H.)
                © The Author 2017. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 10
                Funded by: European Research Council 10.13039/100010663
                Award ID: ERC-2012-AdG 322656-Oculus
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