VARPRISM: incorporating variant prioritization in tests of de novo mutation association. Issue 1 (December 2016)

• Record Type: Journal Article
• Authors: Hu, Hao; Coon, Hilary; Li, Man; Yandell, Mark; Huff, Chad
• Is Part Of: Genome medicine. Volume 8:Issue 1(2016)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-12
• Subjects: De novo mutations -- Autism spectrum disorder -- Simons Simplex Collection -- Likelihood ratio test -- Variant prioritization; Genomics -- Periodicals; Medical genetics -- Periodicals; 616.042
• DOI: 10.1186/s13073-016-0341-9
• Languages: English
• ISSNs: 1756-994X

Abstract

Abstract Background Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates ofde 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 detectde 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, includingMYO1E, KCND3, PDCD1, DLX3, andTSPAN4 (false discovery rate < 0.3). Conclusion By incorporating functional predictions, VARPRISM improved the statistical power to identifyde novo mutations increasing disease risks. VARPRISM is available athttp://www.hufflab.org/software/VARPRISM .