Identification of 23 novel candidate genes for inherited retinal diseases in the European Retinal Disease Consortium

Abstract

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: http://www.erdc.info.

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.