title: The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.
abstract: OBJECTIVE
  This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years.
  
  
  METHODS
  Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis.
  
  
  RESULTS
  Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls.
  
  
  CONCLUSIONS
  The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.
authors.affiliation: NIH Undiagnosed Diseases Program, NIH, Bethesda, Maryland, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.forename: Karin Fuentes
authors.initials: KF
authors.lastname: Fajardo
authors.forename: Murat
authors.initials: M
authors.lastname: Sincan
authors.forename: Fred
authors.initials: F
authors.lastname: Gill
authors.forename: Hannah
authors.initials: H
authors.lastname: Carlson-Donohoe
authors.forename: Andrea
authors.initials: A
authors.lastname: Gropman
authors.forename: Tyler Mark
authors.initials: TM
authors.lastname: Pierson
authors.forename: Gretchen
authors.initials: G
authors.lastname: Golas
authors.forename: Lynne
authors.initials: L
authors.lastname: Wolfe
authors.forename: Catherine
authors.initials: C
authors.lastname: Groden
authors.forename: Rena
authors.initials: R
authors.lastname: Godfrey
authors.forename: Michele
authors.initials: M
authors.lastname: Nehrebecky
authors.forename: Colleen
authors.initials: C
authors.lastname: Wahl
authors.forename: Dennis M D
authors.initials: DM
authors.lastname: Landis
authors.forename: Sandra
authors.initials: S
authors.lastname: Yang
authors.forename: Anne
authors.initials: A
authors.lastname: Madeo
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.forename: David
authors.initials: D
authors.lastname: Adams
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D035843:Biomedical Research; D002648:Child; D002675:Child, Preschool; D002985:Clinical Protocols; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D006078:Government Programs; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009313:National Health Programs; D009316:National Institutes of Health (U.S.); D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D035583:Rare Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D014481:United States; D055815:Young Adult