CommentaryThe NIH Undiagnosed Diseases Program and Network: Applications to modern medicine
Introduction
In 2008, the NIH established an Undiagnosed Diseases Program (UDP), designed to help patients who had long sought a precise diagnosis and to discover new pathways and mechanisms of disease [1], [2], [3]. Ongoing annotation of the human genome, combined with advances in DNA sequencing, provided a huge impetus to the UDP and bolstered the promise of precision medicine [4]. Initiated within the NIH Intramural Research Program, the UDP has now evolved into the Undiagnosed Diseases Network (UDN), supported by the NIH Common Fund. The Network consists of the UDP, six additional clinical sites around the nation, a coordinating center, two DNA sequencing cores, a model organisms screening center, a metabolomics core, and a central biorepository. The UDN functions under a common IRB protocol with reliance agreements and data sharing procedures. On September 16, 2015, the UDN was launched with an online portal for patient applications (https://gateway.undiagnosed.hms.harvard.edu) [5]; it is modeled after the UDP, whose methods and illustrative cases are presented here.
Patients and their families were enrolled in a protocol approved by the NHGRI Institutional Review Board, and gave written informed consent. They applied to the UDP by providing a referral letter from a clinician, along with medical records, laboratory results, imaging studies, and biopsy slides. UDP experts evaluated each application for the presence of objective findings, novel phenotypic manifestations, and the likelihood of obtaining a diagnosis. A signature feature of the UDP was compression of the clinical evaluation at the NIH Clinical Center into five inpatient days, free of charge to the patient, with no insurance approvals. The UDP diagnostic process emphasized highly collaborative clinical evaluations, detailed and standardized documentation of patient's phenotype, and tightly coupled bedside and bench investigations. Standardized documentation of patient phenotypes employed Human Phenotype Ontology (HPO) terms, using PhenoTips software [6]. Clinical consultations were conducted by multiple specialists, and imaging studies and laboratory testing were tailored to the patient's individual manifestations. Examples of specialized assays included cerebrospinal fluid neurotransmitters and plasma glycomics. Biologic samples, including plasma, serum, DNA, urine, and fibroblasts from skin biopsies, were routinely collected and stored. Genetic studies included commercially available testing, panels of genes, single nucleotide polymorphism (SNP) analysis, and family exomic sequencing. Variant analysis utilized both commonly applied variant annotations and manually curated data, including SNP chip correlation, regions of low coverage, and non-coding regions. Some potentially pathogenic variants were evaluated by collaborators using informatics, cultured cell studies, and animal models for functional assays (fly, zebrafish, worm, or mouse).
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Insights from the UDP
From its inception in 2008 through May 2015, the UDP received 2954 complete applications and accepted 863 (29%) for evaluation. Of these, we know 64 (7%) have died. Of the 863 patients evaluated, we present nine vignettes, seven published (Table 1) [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38] and two unpublished, comprising 20 patients in ten families.
Conclusions
Nowhere in medicine have technological advances in diagnostics been as revolutionary as in genetics, where the resolution of human genetic information has increased steadily from the level of chromosomes (karyotyping) to the level of molecules (DNA sequencing). Genomic sequencing now provides vast insights into the individual genetic variations that interact with each person's environment to create health or disease.
Indeed, targeted and agnostic sequencing constitute a huge component of the
Conflicts of interest statement
The authors declare no conflict of interest.
Web resources
The URLs for information presented here are: Online Mendelian Inheritance in Man, http://www.omim.org/, http://www.ncbi.nlm.nih.gov/omim, Human Phenotype Ontology, http://human-phenotype-ontology.github.io/, and Phenotips, https://phenotips.org/.
Acknowledgments
We are deeply indebted to all the patients who entrusted their care to the UDP. The authors appreciate the technical assistance and advice of Jessica Albert, Manfred Boehm, Barbara Burton, Hannah Carlson-Donohoe, Michael Collins, Rachel Gafni, Fred Gill, Rena Godfrey, Gretchen Golas, Catherine Groden, Marjan Huizing, Michele Nehrebecky, Galina Nesterova, Tyler Pierson, Sergio Rosenzweig, Dimitre Simeonov, Stephen F. Traynelis, Zaheer Valivullah, Lynne Wolfe, Hongjie Yuan, Shira G. Ziegler, and
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Other members of the Undiagnosed Diseases Network (UDN): Baylor College of Medicine (C. Bacino, A. Balasubramanyam, H. Bellen, C. Eng, B. Lee, N. Veeraghavan); Columbia University (D. Goldstein); Duke University (V. Shashi, Y.H. Jiang, L. Del Mar Pena); Harvard Medical School (A. Beggs, D. Bernick, C. Brownstein, I. Holm, I. Kohane, J. Loscalzo, C. MacRae, A. McCray, E. Silverman, K. Splinter, J. Stoler, D. Sweetser); Hudson Alpha (H. Jacob, K. Strong, E. Worthey); Illumina Inc. (T. Hambuch); National Human Genome Research Institute (T. Manolio); Oregon University Health Sciences (D. Koeller); Pacific Northwest National Laboratory (T Metz); Stanford University (E. Ashley, J. Bernstein, P. Fisher, M. Wheeler); University of California, Los Angeles (P. Allard, E. Dell'Angelica, K. Dipple, N. Domani, M. Herzog, H. Lee, S. Nelson, C. Palmer, J. Papp, J. Sinsheimer, E. Vilain); Vanderbilt University (J. Cogan, R. Hamid, J. Newman, J.A. Phillips).