The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

Genet Med. 2012 Jan;14(1):51-9. doi: 10.1038/gim.0b013e318232a005. Epub 2011 Sep 26.


Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomedical Research
  • Child
  • Child, Preschool
  • Clinical Protocols
  • DNA Copy Number Variations
  • Exome
  • Female
  • Government Programs*
  • Homozygote
  • Humans
  • Infant
  • Male
  • Middle Aged
  • National Health Programs*
  • National Institutes of Health (U.S.)*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Rare Diseases / diagnosis*
  • Rare Diseases / genetics*
  • Rare Diseases / mortality
  • United States
  • Young Adult