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      Genetic Basis of Inherited Retinal Disease in a Molecularly Characterized Cohort of More Than 3000 Families from the United Kingdom

      , PhD 1 , 2 , , PhD 1 , 2 , 3 , , MD 1 , 2 , , PhD 1 , 2 , , PhD, FRCS(Glasg) 1 , 2 , , BSc 1 , 2 , , MSc 1 , 2 , , MD 1 , 2 , , MSc 2 , , MSc 2 , , BSc 2 , , BSc 2 , , PhD, FRCOphth 1 , 2 , 3 , , PhD, FRCOphth 1 , 2 , 4 , 5 , , MD(Res), FRCOphth 1 , 2 , 6 , , MD(Res), FRCOphth 1 , 2 , , MD(Res), FRCOphth 1 , 2 , , PhD, FRCOphth 1 , 2 , 7 , 8 ,
      IRD, inherited retinal disease, RP, retinitis pigmentosa

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          In a large cohort of molecularly characterized inherited retinal disease (IRD) families, we investigated proportions with disease attributable to causative variants in each gene.


          Retrospective study of electronic patient records.


          Patients and relatives managed in the Genetics Service of Moorfields Eye Hospital in whom a molecular diagnosis had been identified.


          Genetic screening used a combination of single-gene testing, gene panel testing, whole exome sequencing, and more recently, whole genome sequencing. For this study, genes listed in the Retinal Information Network online resource ( https://sph.uth.edu/retnet/) were included. Transcript length was extracted for each gene (Ensembl, release 94).

          Main Outcome Measures

          We calculated proportions of families with IRD attributable to variants in each gene in the entire cohort, a cohort younger than 18 years, and a current cohort (at least 1 patient encounter between January 1, 2017, and August 2, 2019). Additionally, we explored correlation between numbers of families and gene transcript length.


          We identified 3195 families with a molecular diagnosis (variants in 135 genes), including 4236 affected individuals. The pediatric cohort comprised 452 individuals from 411 families (66 genes). The current cohort comprised 2614 families (131 genes; 3130 affected individuals). The 20 most frequently implicated genes overall (with prevalence rates per families) were as follows: ABCA4 (20.8%), USH2A (9.1%), RPGR (5.1%), PRPH2 (4.6%), BEST1 (3.9%), RS1 (3.5%), RP1 (3.3%), RHO (3.3%), CHM (2.7%), CRB1 (2.1%), PRPF31 (1.8%), MY07A (1.7%), OPA1 (1.6%), CNGB3 (1.4%), RPE65 (1.2%), EYS (1.2%), GUCY2D (1.2%), PROM1 (1.2%), CNGA3 (1.1%), and RDH12 (1.1%). These accounted for 71.8% of all molecularly diagnosed families. Spearman coefficients for correlation between numbers of families and transcript length were 0.20 ( P = 0.025) overall and 0.27 ( P = 0.017), –0.17 ( P = 0.46), and 0.71 ( P = 0.047) for genes in which variants exclusively cause recessive, dominant, or X-linked disease, respectively.


          Our findings help to quantify the burden of IRD attributable to each gene. More than 70% of families showed pathogenic variants in 1 of 20 genes. Transcript length (relevant to gene delivery strategies) correlated significantly with numbers of affected families (but not for dominant disease).

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          Most cited references21

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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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            Epidemiology of blindness in children

            An estimated 14 million of the world's children are blind. A blind child is more likely to live in socioeconomic deprivation, to be more frequently hospitalised during childhood and to die in childhood than a child not living with blindness. This update of a previous review on childhood visual impairment focuses on emerging therapies for children with severe visual disability (severe visual impairment and blindness or SVI/BL).For children in higher income countries, cerebral visual impairment and optic nerve anomalies remain the most common causes of SVI/BL, while retinopathy of prematurity (ROP) and cataract are now the most common avoidable causes. The constellation of causes of childhood blindness in lower income settings is shifting from infective and nutritional corneal opacities and congenital anomalies to more resemble the patterns seen in higher income settings. Improvements in maternal and neonatal health and investment in and maintenance of national ophthalmic care infrastructure are the key to reducing the burden of avoidable blindness. New therapeutic targets are emerging for childhood visual disorders, although the safety and efficacy of novel therapies for diseases such as ROP or retinal dystrophies are not yet clear. Population-based epidemiological research, particularly on cerebral visual impairment and optic nerve hypoplasia, is needed in order to improve understanding of risk factors and to inform and support the development of novel therapies for disorders currently considered 'untreatable'.
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              Is Open Access

              Diagnostic exome sequencing in 266 Dutch patients with visual impairment

              Inherited eye disorders have a large clinical and genetic heterogeneity, which makes genetic diagnosis cumbersome. An exome-sequencing approach was developed in which data analysis was divided into two steps: the vision gene panel and exome analysis. In the vision gene panel analysis, variants in genes known to cause inherited eye disorders were assessed for pathogenicity. If no causative variants were detected and when the patient consented, the entire exome data was analyzed. A total of 266 Dutch patients with different types of inherited eye disorders, including inherited retinal dystrophies, cataract, developmental eye disorders and optic atrophy, were investigated. In the vision gene panel analysis (likely), causative variants were detected in 49% and in the exome analysis in an additional 2% of the patients. The highest detection rate of (likely) causative variants was in patients with inherited retinal dystrophies, for instance a yield of 63% in patients with retinitis pigmentosa. In patients with developmental eye defects, cataract and optic atrophy, the detection rate was 50, 33 and 17%, respectively. An exome-sequencing approach enables a genetic diagnosis in patients with different types of inherited eye disorders using one test. The exome approach has the same detection rate as targeted panel sequencing tests, but offers a number of advantages. For instance, the vision gene panel can be frequently and easily updated with additional (novel) eye disorder genes. Determination of the genetic diagnosis improved the clinical diagnosis, regarding the assessment of the inheritance pattern as well as future disease perspective.

                Author and article information

                1 October 2020
                October 2020
                : 127
                : 10
                : 1384-1394
                [1 ]UCL Institute of Ophthalmology, University College London, London, United Kingdom
                [2 ]Genetics Service, Moorfields Eye Hospital, London, United Kingdom
                [3 ]North East Thames Regional Genetics Service, Great Ormond Street Institute of Child Health, London, United Kingdom
                [4 ]Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
                [5 ]Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
                [6 ]Department of Ophthalmology, University of California, San Francisco, San Francisco, California
                [7 ]Section of Ophthalmology, King’s College London, St. Thomas’ Hospital Campus, London, United Kingdom
                [8 ]Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
                Author notes
                []Correspondence: Omar A. Mahroo, PhD, FRCOphth, Moorfields Eye Hospital, 162 City Road, London EC1V 2PD, United Kingdom. o.mahroo@ 123456ucl.ac.uk
                © 2020 by the American Academy of OphthalmologyThis is an open access article under the CC BY license (<inter-ref xlink: href=http://creativecommons.org/licenses/by/4.0/>http://creativecommons.org/licenses/by/4.0/</inter-ref>).

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Original Article

                Ophthalmology & Optometry
                ird, inherited retinal disease,rp, retinitis pigmentosa
                Ophthalmology & Optometry
                ird, inherited retinal disease, rp, retinitis pigmentosa


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