Disease interpretation of regulatory variants with GeneHancer

Whole genome sequencing (WGS) variant analysis and interpretation requires an exploration of non-genic functional genomic elements such as promoters and enhancers, involved in development and implicated in disease. The comprehensive identification of regulatory elements and their gene targets is a significant challenge. We created GeneHancer (PMID:28605766), a regulatory element database within the GeneCards Suite (https://www.genecards.org/), with 400,000 enhancers and promoters. Information is amalgamated from ENCODE, Ensembl, FANTOM5, VISTA, dbSUPER, EPDnew, UCNEbase and GTEx. GeneHancer creates a unique non-redundant and comprehensive view of regulatory elements, including their target gene associations, transcription factor binding sites, tissue specificity and super-enhancer mapping. We recently focus on phenotype/disease annotation of such elements, based on variant-trait mappings from the GWAS Catalog, and literature-curated evidence from DiseaseEnhancer and NCBI Entrez Gene. GeneHancer is now used by a considerable fraction of GeneCards’ 4 million user base to annotate non-coding variants, and was recently included as a native regulation track at the UCSC genome browser, where it is the only source for explicit regulatory regions and gene associations.

GeneHancer provides an indispensable augmentation for the GeneCards’ NGS disease interpretation tools: VarElect, a phenotype interpreter, and TGex, a VCF-to-report analyzer (PMID:27357693), used by major clinical sequencing centers. Non-coding variants are mapped to regulatory regions, and then prioritized with respect to diseases and phenotype keywords via direct and target gene-mediated links. Such capacities provide a comprehensive route to deciphering the clinical significance of non-coding single nucleotide and structural variations, thus helping to elucidate unsolved disease cases.