title: Genome-wide significance testing of variation from single case exomes.
abstract: Standard techniques from genetic epidemiology are ill-suited to formally assess the significance of variants identified from a single case. We developed a statistical inference framework for identifying unusual functional variation from a single exome or genome, what we refer to as the 'n-of-one' problem. Using this approach we assessed our ability to identify the causal genotypes in over 5 million simulated cases of Mendelian disease, identifying 39% of disease genotypes as the most damaging unit in a typical exome background. We applied our approach to 129 n-of-one families from the Undiagnosed Diseases Program, nominating 60% of 30 disease genes determined to be diagnostic by a standard clinical workup. Our method can currently produce well-calibrated P values when applied to single genomes, can facilitate integration of multiple data types for n-of-one analyses, and, with further work, could become a widely used epidemiological method like linkage analysis or genome-wide association analysis.
authors: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Amy B
authors: AB
authors: Wilfert
authors: National Institutes of Health Undiagnosed Diseases Program, US National Institutes of Health, Bethesda, Maryland, USA.
authors: Katherine R
authors: KR
authors: Chao
authors: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Madhurima
authors: M
authors: Kaushal
authors: Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Sanjay
authors: S
authors: Jain
authors: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
authors: Sebastian
authors: S
authors: Zöllner
authors: National Institutes of Health Undiagnosed Diseases Program, US National Institutes of Health, Bethesda, Maryland, USA.
authors: David R
authors: 0000-0002-6660-1242
authors: DR
authors: Adams
authors: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors: Donald F
authors: 0000-0003-3828-8970
authors: DF
authors: Conrad
mesh_terms: D059472:Exome / Q000235:genetics*; D005787:Gene Frequency; D030342:Genetic Diseases, Inborn / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D017422:Sequence Analysis, DNA