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Dror Sharon, Mor Hanany; Allele Frequency Analysis of Variants Reported to cause Autosomal Dominant Retinal Diseases Revealed that 17% of Genes and 9% of Mutations are Unlikely Pathogenic. Invest. Ophthalmol. Vis. Sci. 2019;60(9):2809.
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© ARVO (1962-2015); The Authors (2016-present)
Next generation sequencing (NGS) techniques generate a large amount of genetic data that can be used to better characterize the set of disease-causing mutations in the human genome. The vast majority of variants identified in NGS analyses are “incidental” or “secondary” findings, previously termed as “incidentalome”. Our aim was to analyze allele frequencies values of sequence variants that were reported to cause autosomal dominant inherited retinal diseases (AD-IRDs) and examine if there are reported mutations and genes that are unlikely to be pathogenic.
The genetic information was collected from various databases: reported AD-IRD mutations from PubMed publications and the Human Genome Mutation Database (HGMD), a list of AD-IRD genes from RETNET, allele frequencies from gnomAD, mutation nomenclature from Mutalyzer, and data published regarding segregation analysis and biochemical effect of specific variants on protein function.
We generated a database gathering information on 1,229 variants reported to cause AD-IRDs in 58 genes. While the majority of variants (83%) are not represented in gnomAD, 113 (9%) were found in more than one individual and had a carrier frequency of over 1:100,000. Interestingly, in some cases, these unlikely pathogenic variants were the only ones reported to cause disease in AD inheritance pattern for a particular gene, therefore raising doubt regarding the involvement of 10 (17%) of the genes as AD-IRD causing genes. After excluding the reported mutations that are unlikely pathogenic, our analysis revealed 1100 reported mutations in 48 genes as the cause of nonsyndromic AD-IRDs.
We predict that these data are not limited to a specific disease or inheritance pattern since previous reports indicated that nonpathogenic variants were mistakenly reported as pathogenic mutations in various diseases. To the best of our knowledge, the current study represents the first systematic analysis of autosomal dominant sequence variants reported to cause a specific, yet heterogeneous, disease. Our results should serve as a warning sign for geneticists, mutation database curators, and sequencing panels’ developers not to automatically accept reported mutations as pathogenic, but cross-reference the information with large NGS-based databases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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