VARPRISM: incorporating variant prioritization in tests of de novo mutation association

BACKGROUND: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes. RESULTS: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3). CONCLUSION: By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-016-0341-9) contains supplementary material, which is available to authorized users.