title: VARPRISM: incorporating variant prioritization in tests of de novo mutation association.
abstract: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes.
  
  
  
  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).
  
  
  
  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 .
authors: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
authors: Hao
authors: H
authors: Hu
authors: Department of Psychiatry, University of Utah, Salt Lake City, UT, USA.
authors: Hilary
authors: H
authors: Coon
authors: Department of Human Genetics and USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA.
authors: Man
authors: M
authors: Li
authors: Department of Human Genetics and USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA.
authors: Mark
authors: M
authors: Yandell
authors: Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. chuff1@mdanderson.org.
authors: Chad D
authors: CD
authors: Huff
mesh_terms: D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D059472:Exome; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D009154:Mutation; D024461:Myosin Type I / Q000235:genetics; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D051672:Shal Potassium Channels / Q000235:genetics; D012984:Software; D059470:Tetraspanins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; C497021:KCND3 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D051672:Shal Potassium Channels; C109139:TSPAN4 protein, human; D059470:Tetraspanins; D014157:Transcription Factors; C511011:MYO1E protein, human; D024461:Myosin Type I
keywords: Autism spectrum disorder; De novo mutations; Likelihood ratio test; Simons Simplex Collection; Variant prioritization