The national institutes of health undiagnosed diseases program: Insights into rare diseases

William A. Gahl, Thomas C. Markello, Camilo Toro, Karin Fuentes Fajardo, Murat Sincan, Fred Gill, Hannah Carlson-Donohoe, Andrea Gropman, Tyler Mark Pierson, Gretchen Golas, Lynne Wolfe, Catherine Groden, Rena Godfrey, Michele Nehrebecky, Colleen Wahl, Dennis M.D. Landis, Sandra Yang, Anne Madeo, James C. Mullikin, Cornelius F. BoerkoelCynthia J. Tifft, David Adams

Research output: Contribution to journalArticlepeer-review

229 Scopus citations


Purpose: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Programs application of genomic technology to establish diagnoses, and details the Programs 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.

Original languageEnglish (US)
Pages (from-to)51-59
Number of pages9
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 1 2012
Externally publishedYes


  • SNP arrays
  • neurological disorders
  • rare disease
  • undiagnosed disease
  • whole exome sequencing

ASJC Scopus subject areas

  • Genetics(clinical)


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