title: PERCH: A Unified Framework for Disease Gene Prioritization.
abstract: To interpret genetic variants discovered from next-generation sequencing, integration of heterogeneous information is vital for success. This article describes a framework named PERCH (Polymorphism Evaluation, Ranking, and Classification for a Heritable trait), available at http://BJFengLab.org/. It can prioritize disease genes by quantitatively unifying a new deleteriousness measure called BayesDel, an improved assessment of the biological relevance of genes to the disease, a modified linkage analysis, a novel rare-variant association test, and a converted variant call quality score. It supports data that contain various combinations of extended pedigrees, trios, and case-controls, and allows for a reduced penetrance, an elevated phenocopy rate, liability classes, and covariates. BayesDel is more accurate than PolyPhen2, SIFT, FATHMM, LRT, Mutation Taster, Mutation Assessor, PhyloP, GERP++, SiPhy, CADD, MetaLR, and MetaSVM. The overall approach is faster and more powerful than the existing quantitative method pVAAST, as shown by the simulations of challenging situations in finding the missing heritability of a complex disease. This framework can also classify variants of unknown significance (variants of uncertain significance) by quantitatively integrating allele frequencies, deleteriousness, association, and co-segregation. PERCH is a versatile tool for gene prioritization in gene discovery research and variant classification in clinical genetic testing.
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, Utah.|Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Bing-Jian
authors.initials: BJ
authors.lastname: Feng
mesh_terms: D019295:Computational Biology / Q000379:methods*; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012372:ROC Curve; D015203:Reproducibility of Results; D012984:Software
keywords: co-segregation analysis; de novo mutation; functional consequence; gene association network; gene prioritization; genetic testing; rare-variant burden test; variant interpretation; variants of unknown significance; whole-exome/whole-genome/gene-panel sequencing