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

Galuh Astuti,Manir Ali,Lonneke Haer-Wigman,Susanne Roosing,Christian Hamel,Martin Mckibbin,Mohammed El-Asrag,Gaël Manes,Frans Cremers,Graeme Black,Carmel Toomes,Béatrice Bocquet,Chris Inglehearn,Mathieu Quinodoz,L Van Den Born,M Khan,Carel Hoyng

doi:10.3390/genes9010021

Abstract

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.

Highlights

Inherited retinal diseases (IRDs) comprise of a clinically and genetically heterogeneous group of hereditary retinal degenerations, which affect around 1 in 3000 people
We performed an assessment to predict the pathogenicity of selected candidate variants by combining: (a) minor allele frequency (ExAC); (b) in silico prediction program (CADD score); (c) whether there is any interaction with retinal-associated protein
We implemented the American College of Medical Genetics (ACMG) guidelines to predict variants based on their pathogenicity [28]

Summary

Introduction

Inherited retinal diseases (IRDs) comprise of a clinically and genetically heterogeneous group of hereditary retinal degenerations, which affect around 1 in 3000 people. Inherited Retinal Diseases are one of the leading causes of vision loss in young individuals in the developed countries, with a significant impact on patients and society [1,2,3]. The spectrum of genotyping technologies employed in the last three decades, ranging from positional cloning, (mouse) candidate disease gene analyses, linkage analysis, homozygosity mapping, and whole exome sequencing (WES) have led to a wide body of knowledge regarding the molecular genetics of IRDs. Currently, mutations in 261 genes have been discovered to be involved in IRDs [7]. Two WES studies in the Saudi-Arabian and the Dutch population showed that only ~3–4% of IRD cases carry variants in novel IRD-associated genes [8,9,10,11,12]. Finding additional cases carrying variant(s) in the same candidate gene is often challenging

Methods

Results

Conclusion