Calculating the statistical significance of rare variants causal for Mendelian and complex disorders

With the expanding use of next-gen sequencing (NGS) to diagnose the thousands of rare Mendelian genetic diseases, it is critical to be able to interpret individual DNA variation. We developed a general method to better interpret the likelihood that a rare variant is disease causing if observed in a given gene or genic region mapping to a described protein domain, using genome-wide information from a large control sample. We implemented these methods as a web tool and demonstrate application to 19 relevant but diverse next-gen sequencing studies. Additionally, we calculate the statistical significance of findings involving multi-family studies with rare Mendelian disease and studies of large-scale complex disorders such as autism spectrum disorder.