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Genes 2018, 9(1), 21; doi:10.3390/genes9010021

Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes

Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
Radboud Institute for Molecular Life Sciences, Radboud University, 6525 GA Nijmegen, The Netherlands
The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands
Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EN Nijmegen, The Netherlands
Institut National de la Santé et de la Recherche Médicale, Institute for Neurosciences of Montpellier, 34080 Montpellier, France
University of Montpellier, 34090 Montpellier, France
CHRU, Genetics of Sensory Diseases, 34295 Montpellier, France
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1015 Lausanne, Switzerland
Section of Ophthalmology & Neuroscience, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, St. James’s University Hospital, LS9 7TF Leeds, UK
Department of Ophthalmology, St. James’s University Hospital, LS9 7TF Leeds, UK
Department of Zoology, Faculty of Science, Benha University, 13511 Benha, Egypt
Centre for Genomic Medicine, St. Mary’s Hospital, Manchester Academic Health Science Centre, University of Manchester, M13 9PL Manchester, UK
Department of Ophthalmology, Radboud University Medical Center, 6525 EX Nijmegen, The Netherlands
We would like to dedicate this manuscript to Prof. Christian P. Hamel (C.P.H.), who recently passed away.
Author to whom correspondence should be addressed.
Received: 20 October 2017 / Revised: 31 December 2017 / Accepted: 3 January 2018 / Published: 10 January 2018
View Full-Text   |   Download PDF [3059 KB, uploaded 10 January 2018]   |  


Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 (SNRNP200) and Zinc Finger Protein 513 (ZNF513), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 (DHX32) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed. View Full-Text
Keywords: whole exome sequencing; inherited retinal diseases; candidate retinal disease genes whole exome sequencing; inherited retinal diseases; candidate retinal disease genes

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Astuti, G.D.N.; van den Born, L.I.; Khan, M.I.; Hamel, C.P.; Bocquet, B.; Manes, G.; Quinodoz, M.; Ali, M.; Toomes, C.; McKibbin, M.; El-Asrag, M.E.; Haer-Wigman, L.; Inglehearn, C.F.; Black, G.C.M.; Hoyng, C.B.; Cremers, F.P.M.; Roosing, S. Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes. Genes 2018, 9, 21.

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