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

Galuh D N Astuti, L Ingeborgh van den Born, M Imran Khan, Christian P Hamel, Béatrice Bocquet, Gaël Manes, Mathieu Quinodoz, Manir Ali, Carmel Toomes, Martin McKibbin, Mohammed E El-Asrag, Lonneke Haer-Wigman, Chris F Inglehearn, Graeme C M Black, Carel B Hoyng, Frans P M Cremers, Susanne Roosing

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
JournalGenes
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Jan 2018

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  • Cite this

    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. (2018). Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes. Genes, 9(1). https://doi.org/10.3390/genes9010021