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Allele frequency analysis of variants reported to cause autosomal dominant inherited retinal diseases question the involvement of 19% of genes and 10% of reported pathogenic variants
  1. Mor Hanany,
  2. Dror Sharon
  1. Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  1. Correspondence to Professor Dror Sharon, Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; dror.sharon1{at}


Background Next generation sequencing (NGS) generates a large amount of genetic data that can be used to better characterise disease-causing variants. Our aim was to examine allele frequencies of sequence variants reported to cause autosomal dominant inherited retinal diseases (AD-IRDs).

Methods Genetic information was collected from various databases, including PubMed, the Human Genome Mutation Database, RETNET and gnomAD.

Results We generated a database of 1223 variants reported in 58 genes, including their allele frequency in gnomAD that contains NGS data of over 138 000 individuals. While the majority of variants are not represented in gnomAD, 138 had an allele count of >1 and were examined carefully for various aspects including cosegregation and functional analyses. The analysis revealed 122 variants that were reported pathogenic but unlikely to cause AD-IRDs. 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 11 (19%) of the genes in AD-IRDs.

Conclusion We predict that these data are not limited to a specific disease or inheritance pattern since non-pathogenic variants were mistakenly reported as pathogenic in various diseases. Our results should serve as a warning sign for geneticists, variant database curators and sequencing panels’ developers not to automatically accept reported variants as pathogenic but cross-reference the information with large databases.

  • minor allele frequency
  • autosomal dominant
  • pathogenic variant
  • inherited retinal diseases

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  • Contributors MH and DS planned the study, performed data analysis, drafted and revised the manuscript. DS obtained funding and is responsible for the overall content of the study.

  • Funding This study was funded by the Israeli Ministry of Health (grant numbers 3-10999 and 3-12583) and the Foundation Fighting Blindness (grant number BR-GE-0518-0734).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.