The National Institutes of Health Undiagnosed Diseases Program (UDP): The First Four Years. D. R. Adams1,2, C. F. Boerkoel1, R. Godfrey1, G. Golas1, C. Groden1, A. Gropman3, D. Landis1, T. C. Markello1, M. Nehrebecky1, T. Pierson4, M. Sincan1, C. J. Tifft1,5, C. Toro1, C. Wahl1, L. Wolfe1, W. A. Gahl1,2,5 1) Undiagnosed Diseases Program, NIH; 2) Medical Genetics Branch, NGHRI/NIH; 3) Children's National Medical Center, Washington, DC; 4) Departments of Pediatrics and Neurology, Cedars-Sinai, Los Angeles, CA; 5) Office of the Clinical Director, NHGRI, NIH, Bethesda, MD.
The NIH UDP was started in 2008 to diagnose and further investigate persons who remain undiagnosed despite an extensive medical workup. The UDP is currently developing a national network of similar sites. We reviewed progress toward our original goals, and examined the cohort of individuals accepted into the program to date. The UDP has received 7000 inquiries, reviewed 2800 medical records, and accepted 640 participants since 2008. Participants were selected based on objective findings, safety considerations, and available expertise. Selection criteria evolved over time, balancing the need to serve a diverse population with an understanding of the characteristics of potentially tractable cases. Evaluations included review of medical records, in-person medical testing, and specialty consultation. Cases remaining undiagnosed after the initial visit were evaluated for potential transition to research, and the medical workup was designed to clarify the quantifiable portions of the medical presentation. Applicants were classified into 21 broad categories; half of the cases were neurological; 56% were female; 33% were pediatric. Some diagnosis was offered in 24% of the evaluated cohort, ranging from descriptive to definitive. Exome sequencing was performed on 480 individuals (150 probands). In the pediatric cohort, 17 diagnoses were made by exome or SNP-array analysis, while 17 were made by conventional methods. Two new diseases were published and > 30 new-disease candidates are under ongoing study. At least seven cases resulted in treatments. Five new clinical protocols have arisen as a result of UDP evaluations. Evaluation of exome data from UDP patients has resulted in the development of new exome analysis approaches and technologies. There is a substantial population with undiagnosed, severe medical conditions. Most initial evaluations do not generate a definitive diagnosis. The majority of persons with undiagnosed disease, therefore, require a process for transition to medical research. To that end, future efforts will focus on refining such processes, including the creation of standardized phenotypic descriptions, the incorporation of novel hypothesis-generating screens, and the development of online collaboration tools to facilitate information sharing among clinicians, researchers and affected families.
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