GeneBreaker - Variant simulation to improve the diagnosis of Mendelian rare genetic diseases

Abstract Mendelian rare genetic diseases affect 5-10% of the population, and with over 5,300 genes responsible for ～7,000 different diseases, they are challenging to diagnose. The use of whole genome sequencing (WGS) for patients and families affected by rare diseases has bolstered the diagnosis rate significantly. Effective use of WGS in this setting relies on the ability to identify the “broken” gene responsible for the disease phenotype. This process involves genomic variant calling and prioritization, and is the beneficiary of rapid improvements to sequencing technology, variant calling approaches, and increased capacity to predict and prioritize genetic variants with potential pathogenicity. As analysis pipelines continue to improve and genomic medicine moves toward a standard of care, careful testing of their efficacy is paramount. However, real-life cases typically emerge anecdotally, and utilization of patient data for the purpose of testing pipeline improvements is regulated and limiting. We identified the need for a gene-based variant simulation framework which can create mock rare disease scenarios, utilizing known pathogenic variants or through the creation of novel gene-disrupting variants. To fill this need, we present GeneBreaker, a tool which creates synthetic rare disease cases with utility for benchmarking variant calling approaches, testing the efficacy of variant prioritization, and as an educational mechanism for the training of diagnostic practitioners in the rapidly growing field of genomic medicine. GeneBreaker is freely available at http://GeneBreaker.cmmt.ubc.ca.