title: Detecting false-positive signals in exome sequencing.
abstract: Disease gene discovery has been transformed by affordable sequencing of exomes and genomes. Identification of disease-causing mutations requires sifting through a large number of sequence variants. A subset of the variants are unlikely to be good candidates for disease causation based on one or more of the following criteria: (1) being located in genomic regions known to be highly polymorphic, (2) having characteristics suggesting assembly misalignment, and/or (3) being labeled as variants based on misleading reference genome information. We analyzed exome sequence data from 118 individuals in 29 families seen in the NIH Undiagnosed Diseases Program (UDP) to create lists of variants and genes with these characteristics. Specifically, we identified several groups of genes that are candidates for provisional exclusion during exome analysis: 23,389 positions with excess heterozygosity suggestive of alignment errors and 1,009 positions in which the hg18 human genome reference sequence appeared to contain a minor allele. Exclusion of such variants, which we provide in supplemental lists, will likely enhance identification of disease-causing mutations using exome sequence data.
authors.affiliation: NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research and NHGRI, Bethesda, Maryland, USA.
authors.forename: Karin V
authors.initials: KV
authors.lastname: Fuentes Fajardo
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.forename: Murat
authors.initials: M
authors.lastname: Sincan
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tifft
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.forename: William
authors.initials: W
authors.lastname: Gahl
authors.forename: Thomas
authors.initials: T
authors.lastname: Markello
mesh_terms: D059472:Exome; D005189:False Positive Reactions; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D009316:National Institutes of Health (U.S.); D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D014481:United States