title: Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency.
abstract: Medical diagnosis and molecular or biochemical confirmation typically rely on the knowledge of the clinician. Although this is very difficult in extremely rare diseases, we hypothesized that the recording of patient phenotypes in Human Phenotype Ontology (HPO) terms and computationally ranking putative disease-associated sequence variants improves diagnosis, particularly for patients with atypical clinical profiles.
  
  
  
  Using simulated exomes and the National Institutes of Health Undiagnosed Diseases Program (UDP) patient cohort and associated exome sequence, we tested our hypothesis using Exomiser. Exomiser ranks candidate variants based on patient phenotype similarity to (i) known disease-gene phenotypes, (ii) model organism phenotypes of candidate orthologs, and (iii) phenotypes of protein-protein association neighbors.
  
  
  
  Benchmarking showed Exomiser ranked the causal variant as the top hit in 97% of known disease-gene associations and ranked the correct seeded variant in up to 87% when detectable disease-gene associations were unavailable. Using UDP data, Exomiser ranked the causative variant(s) within the top 10 variants for 11 previously diagnosed variants and achieved a diagnosis for 4 of 23 cases undiagnosed by clinical evaluation.
  
  
  
  Structured phenotyping of patients and computational analysis are effective adjuncts for diagnosing patients with genetic disorders.Genet Med 18 6, 608-617.
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Bone
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Washington
authors.affiliation: Centre for Computational Medicine Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Orion J
authors.identifier: 0000-0002-9064-092X
authors.initials: OJ
authors.lastname: Buske
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: David
authors.initials: D
authors.lastname: Draper
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Elise D
authors.identifier: 0000-0003-0221-8196
authors.initials: ED
authors.lastname: Flynn
authors.affiliation: Centre for Computational Medicine Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marta
authors.identifier: 0000-0002-8666-5446
authors.initials: M
authors.lastname: Girdea
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rena
authors.initials: R
authors.lastname: Godfrey
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Groden
authors.affiliation: Skarnes Faculty group, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Julius
authors.initials: J
authors.lastname: Jacobsen
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Köhler
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Elizabeth M J
authors.initials: EM
authors.lastname: Lee
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Amanda E
authors.identifier: 0000-0002-9307-2403
authors.initials: AE
authors.lastname: Links
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mungall
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Nehrebecky
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Sincan
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ariane G
authors.initials: AG
authors.lastname: Soldatos
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: Cynthia J
authors.identifier: 0000-0002-3931-1207
authors.initials: CJ
authors.lastname: Tifft
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.affiliation: Centre for Computational Medicine Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Trang
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Elise
authors.identifier: 0000-0003-4624-4732
authors.initials: E
authors.lastname: Valkanas
authors.affiliation: Library; and Department of Medical Informatics and Epidemiology, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Nicole
authors.identifier: 0000-0001-5208-3432
authors.initials: N
authors.lastname: Vasilevsky
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Wahl
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Cornelius F
authors.identifier: 0000-0003-3097-241X
authors.initials: CF
authors.lastname: Boerkoel
authors.affiliation: Centre for Computational Medicine Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Brudno
authors.affiliation: Library; and Department of Medical Informatics and Epidemiology, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Haendel
authors.affiliation: Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland, USA.|Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Skarnes Faculty group, Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Damian
authors.initials: D
authors.lastname: Smedley
mesh_terms: D000818:Animals; D019295:Computational Biology; D030541:Databases, Genetic; D004195:Disease Models, Animal; D059472:Exome / Q000235:genetics*; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D009316:National Institutes of Health (U.S.); D010361:Patients; D010641:Phenotype; D035583:Rare Diseases / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D014481:United States; D000073359:Exome Sequencing / Q000379:methods*; D015027:Zebrafish