Background: Analysis of variants in distant regulatory elements could improve the current 25-50% yield of genetic testing for monogenic diseases. However, the vast size of the regulome, great number of variants, and the difficulty in predicting their phenotypic impact make searching for pathogenic variants in the regulatory genome challenging. New tools for the identification of regulatory variants based on their relevance to the phenotype are needed.
Methods: We used tissue-specific regulatory loci mapped by ENCODE and FANTOM, together with miRNA-gene interactions from miRTarBase and miRWalk, to develop Remus, a web application for the identification of tissue-specific regulatory regions. Remus searches for regulatory features linked to the known disease-associated genes and filters them using activity status in the target tissues relevant for the studied disorder. For user convenience, Remus provides a web interface and facilitates in-browser filtering of variant files suitable for sensitive patient data.
Results: To evaluate our approach, we used a set of 146 regulatory mutations reported causative for 68 distinct monogenic disorders and a manually curated a list of tissues affected by these disorders. In 89.7% of cases, Remus identified the regulator containing the pathogenic mutation. The tissue-specific search limited the number of considered variants by 82.5% as compared to a tissue-agnostic search.
Conclusion: Remus facilitates the identification of regulatory regions potentially associated with a monogenic disease and can supplement classical analysis of coding variations with the aim of improving the diagnostic yield in whole-genome sequencing experiments.
Keywords: monogenic disorder; regulatory regions; regulatory variants; variant prioritization; web application; whole-genome sequencing.
Copyright © 2021 Sztromwasser, Skrzypczak, Michalak and Fendler.