September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Identification of 23 novel candidate genes for inherited retinal diseases in the European Retinal Disease Consortium
Author Affiliations & Notes
  • Galuh D.N. Astuti
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
    Center for Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University, Semarang, Indonesia
  • Tamar Ben-Yosef
    The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
  • Susanne Kohl
    Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany
  • Rando Allikmets
    Pathology and Cell Biology, Columbia University, New York, New York, United States
  • Graeme C.M. Black
    Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Saint Mary's Hospital, Manchester, United Kingdom
  • Shomi S Bhattacharya
    Institute of Ophthalmology, University College London, London, United Kingdom
  • Christian P Hamel
    INSERM, U-1051, Institut des Neurosciences, Université de Montpellier, Montpellier, France
  • M Imran Khan
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  • Lonneke Haer-Wigman
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  • Frans P Cremers
    Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
  • Footnotes
    Commercial Relationships   Galuh Astuti, None; Tamar Ben-Yosef, None; Susanne Kohl, None; Rando Allikmets, None; Graeme Black, None; Shomi Bhattacharya, None; Christian Hamel, None; M Imran Khan, None; Lonneke Haer-Wigman, None; Frans Cremers, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Galuh D.N. Astuti, Tamar Ben-Yosef, Susanne Kohl, Rando Allikmets, Graeme C.M. Black, Shomi S Bhattacharya, Christian P Hamel, M Imran Khan, Lonneke Haer-Wigman, Frans P Cremers; Identification of 23 novel candidate genes for inherited retinal diseases in the European Retinal Disease Consortium. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : The introduction of next generation sequencing contributed to the identification of causal variants in ‘novel’ inherited retinal disease (IRD)-associated genes and enabled the sequence analysis of 142 genes implicated in non-syndromic IRDs. As we estimate that more than 90% of the ‘IRD-disease load’ resides in these 142 genes, identifying novel candidate genes for IRD becomes challenging. By sharing whole exome sequencing (WES) data and homozygosity mapping data within the European Retinal Disease Consortium (ERDC; 15 research groups in 11 countries), mutations in several genes were identified in multiple unrelated IRD cases. In addition, candidate causal variants were found in many single cases with IRD. In this study we aim to: (1) assess the causality of these candidate genes, (2) search for novel genotype-phenotype correlations and (3) investigate different inheritance patterns for variants in known IRD-associated genes.

Methods : WES was performed in individuals affected with IRDs. Prioritization of candidate genes was based on: (1) allele frequency of the variant in ExAC, (2) pathogenicity assessment using the Combined Annotation Dependent Depletion (CADD) score, (3) its involvement in a retinal pathway and (4) interaction with known IRD-associated proteins.

Results : Firstly, rare variants were identified in 23 potentially causative genes. Variants in 22 genes (85%) had a CADD score >15; 10 genes are known to be involved in retinal pathways and 8 genes encode proteins that interact with known IRD-associated proteins. Using the aforementioned criteria, CALHM3, IDH3A and TMED7 are the top ranked candidate genes. Secondly, we identified novel IFT140-variants to be associated with non-syndromic retinitis pigmentosa (RP). Thirdly, a novel homozygous SNRNP200 variant was associated with autosomal recessive RP and a novel ZNF513 variant was found in an autosomal dominant RP family. These candidate genes are listed in the ERDC website:

Conclusions : WES studies increasingly reveal candidate genes in single IRD cases. Without the identification of variants in these genes in unrelated cases or without animal modeling studies, the association of these genes with IRD remains uncertain. Through this study and a continuous update of novel candidate IRD genes in an open access website, we aim to accelerate the identification of rarely mutated IRD-associated genes.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.


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