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Review
. 2014 Dec;26(6):626-33.
doi: 10.1097/MOP.0000000000000155.

The National Institutes of Health undiagnosed diseases program

Cynthia J Tifft  1 , David R Adams
Affiliations
Review

The National Institutes of Health undiagnosed diseases program

Cynthia J Tifft et al. Curr Opin Pediatr. 2014 Dec.

Abstract

Purpose of review: To review the approach to undiagnosed patients and results of the National Institutes of Health (NIH) undiagnosed diseases program (UDP), and discuss its benefits to patients, academic medical centers, and the greater scientific community.

Recent findings: The NIH UDP provides comprehensive and collaborative evaluations for patients with objective findings of disease whose diagnoses have long eluded the medical community. Intensive review of patient records, careful phenotyping, and new genomic technologies have resulted in the diagnosis of new and extremely rare conditions, expanded the phenotypes of rare disorders, and determined that symptoms are caused by more than one disorder in a family.

Summary: Many children and adults with complex phenotypes remain undiagnosed despite years of searching. The most common undiagnosed disorders involve a neurologic phenotype. Comprehensive phenotyping and genomic analysis utilizing nuclear families can provide a diagnosis in some cases and provide good 'lead' candidate genes for others. A UDP can be important for patients, academic medical centers, the scientific community, and society.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
The graph indicates the age of pediatric patients at the time of application to the UDP. The first peak represents the congenital onset disease (applicants’ age 4–6 years) and the second peak represents the onset of disease symptoms at early school age (applicants’ age 16–18 years). The time between the onset of symptoms and the time of application indicates the lengthy diagnostic odyssey experienced by most UDP patients. UDP, Undiagnosed Diseases Program.
FIGURE 2
FIGURE 2
Evaluation of a pediatric patient with a neurological phenotype. aModified from [3▪▪], Table 83-2.
See this image and copyright information in PMC

References

    1. Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011;305:1904–1905. - PubMed
    1. Gahl WA, Markello TC, Toro C, et al. The NIH Undiagnosed Diseases Program: insights into rare diseases. Genet Med. 2013;14:51–59. This article summarizes the first 2 years of the UDP experience, including approach to diagnosis, techniques used in phenotype and genotype analysis, and chronicles the rare and very rare disorders identified through the UDP. - PMC - PubMed
    1. Gahl WA, Adams DR, Markello TC, et al. Genetic approaches to rare and undiagnosed diseases. In: Kliegman RM, Stanton BF, St Geme J, Schor N, editors. Nelson’s textbook of pediatrics. 20. Chapter 82. Philadelphia, PA: Elsevier, Inc; 2014. This chapter is a summary of the UDP, particularly as it relates to the pediatric patient. It outlines a comprehensive approach to the evaluation of the child with neurologic or neurodegenerative disease, describes the genomic analysis of the proband and the nuclear family using single-nucleotide polymorphism arrays and whole-exome sequencing, and details the sample collection for functional studies of novel candidate genes.
    1. Kircher M, Witten DM, Jain P, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–315. - PMC - PubMed
    1. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med. 2013;369:1502–1511. This original study presents the diagnostic results of the first 250 probands, for whom whole-exome sequencing was performed in a clinical laboratory setting. - PMC - PubMed

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