The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine

doi:10.1016/j.ymgme.2016.01.007

Molecular Genetics and Metabolism

Volume 117, Issue 4, April 2016, Pages 393-400

https://doi.org/10.1016/j.ymgme.2016.01.007 Get rights and content

Highlights

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In 7 years, NIH’s Undiagnosed Diseases Program saw 863 individuals, undiagnosed after thorough evaluation elsewhere.
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After record review, a one-week hospitalization included multiple consultations, targeted tests, and DNA sequencing.
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9 vignettes with 20 patients illustrate successful diagnoses including arterial calcification due to deficiency of CD73.
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The vignettes show relevance to common disorders, newly recognized disease mechanisms and the future of precision medicine.

Abstract

Introduction

The inability of some seriously and chronically ill individuals to receive a definitive diagnosis represents an unmet medical need. In 2008, the NIH Undiagnosed Diseases Program (UDP) was established to provide answers to patients with mysterious conditions that long eluded diagnosis and to advance medical knowledge.

Patients admitted to the NIH UDP undergo a five-day hospitalization, facilitating highly collaborative clinical evaluations and a detailed, standardized documentation of the individual's phenotype. Bedside and bench investigations are tightly coupled. Genetic studies include commercially available testing, single nucleotide polymorphism microarray analysis, and family exomic sequencing studies. Selected gene variants are evaluated by collaborators using informatics, in vitro cell studies, and functional assays in model systems (fly, zebrafish, worm, or mouse).

Insights from the UDP

In seven years, the UDP received 2954 complete applications and evaluated 863 individuals. Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in individual patients, newly recognized mechanisms of disease, and the application of precision medicine to patient care.

Conclusions

The UDP provides examples of the benefits expected to accrue with the recent launch of a national Undiagnosed Diseases Network (UDN). The UDN should accelerate rare disease diagnosis and new disease discovery, enhance the likelihood of diagnosing known diseases in patients with uncommon phenotypes, improve management strategies, and advance medical research.

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).

Section snippets

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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XMEN (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV), and N-linked glycosylation defect) disease results from loss-of-function mutations in MAGT1, a protein that serves as a magnesium transporter and a subunit of the oligosaccharyltransferase (OST) complex. MAGT1 deficiency disrupts N-linked glycosylation, a critical regulator of immune function. XMEN results in recurrent EBV infections and a propensity for EBV-driven malignancies. Although XMEN is recognized as a systemic congenital disorder of glycosylation (CDG), its neurological involvement is rare and poorly characterized.
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From 2008 to 2020, 249 pediatric patients in the UDP underwent anesthesia for diagnostic procedures. The majority had a severe systemic disease (American Society for Anesthesiology status III, 79%) and/or a neurologic condition (91%). Perioperative events occurred in 45 patients; six of these were attributed to anesthesia. All patients recovered fully without sequelae. Nearly half of the 249 patients (49%) received a diagnosis, and almost all these diagnoses (88%) took advantage of information gleaned from procedures performed under anesthesia.
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¹: 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).

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CommentaryThe NIH Undiagnosed Diseases Program and Network: Applications to modern medicine

Highlights

Abstract

Introduction

Insights from the UDP

Conclusions

Introduction

Section snippets

Insights from the UDP

Conclusions

Conflicts of interest statement

Web resources

Acknowledgments

Genet. Med.

Neuromuscul. Disord.

Mol. Genet. Metab.

Neuromuscul. Disord.

Mol. Genet. Metab.

Pediatr. Neurol.

Mol. Genet. Metab.

Mol. Genet. Metab.

Am. J. Hum. Genet.

Mol. Genet. Metab.

Am. J. Hum. Genet.

Biochem. Biophys. Res. Commun.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Mol. Genet. Metab.

Mol. Genet. Metab.

Genet. Med.

Mol. Genet. Metab.

The NIH Undiagnosed Diseases Program: lessons learned

JAMA

The National Institutes of Health Undiagnosed Diseases Program

Curr. Opin. Pediatr.

A new initiative on precision medicine

N. Engl. J. Med.

The Undiagnosed Diseases Network of the NIH: a national extension

JAMA

Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency

Genet. Med.

NT5E mutations and arterial calcifications

N. Engl. J. Med.

Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases

PLoS Genet.

Exome sequencing and SNP analysis detect heterozygosity in fatty acid hydroxylase-associated neurodegeneration

Eur. J. Hum. Genet.

IgG4-related disease presenting as recurrent mastoiditis

Laryngoscope

Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis

Neurology

1,25-(OH)2D-24 hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis

Clin. J. Am. Soc. Nephrol.

Kearns-Sayre syndrome presenting as isolated growth failure

BMJ Case Rep.

Commentary
The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine

1,25-(OH)₂D-24 hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis