The NIH Undiagnosed Diseases Program and Network: Applications to modern 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 Nine vignettes (two unpublished) illustrate the relevance of an undiagnosed diseases program to complex and common disorders, the coincidence of multiple rare single gene disorders in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.

Keywords: Exome sequencing; Interdisciplinary research; Precision medicine; Undiagnosed and rare diseases.

Fig. 1

Understanding common and complex diseases. (A) Gracile, osteoporotic tibia and fibula. (B) Polyamine synthetic pathway. Addition of a propylamine moiety from decarboxylated S-adenosylmethionine to putrescine produces spermidine. A second propylamine moiety is added to spermidine by spermine synthase, producing spermine. Spermine synthase is deficient in boys with Snyder-Robinson syndrome. Spermidine and spermine are polyamines whose ratio is crucial for cell processes including transcription and translation [39]. (C) Pathway defective in Congenital Disorder of Glycosylation IIb. Glucosidase I, deficient in the disorder, catalyzes the first step in the conversion of high mannose glycoproteins to complex glycoproteins, as part of the endoplasmic reticulum protein quality control process, also known as the unfolded protein response. (D) Viral infections in patient cells. Glycosylated viruses such as HIV can infect these cells, but the cells produce viruses that contain an abnormally glycosylated coat, making them less infective. No differences in terms of infectivity were noted when non-glycosylated viruses were tested. (Courtesy of Dr. Sergio D. Rosenzweig.)

Fig. 2

Coincidental rare Mendelian diseases: Dulling Occam’s razor. (A) Brother (left) and sister (right) with Brown-Vialetto-van Laere syndrome type 2, distal renal tubular acidosis, hearing loss, and mitochondrial topoisomerase 1 deficiency. (B) The family pedigree; double line indicates consanguinity. There were seven previous spontaneous abortions. Below each patient symbol is a list of that individual’s pertinent gene variants. The table lists the genes and the family’s associated diseases, all recessive disorders. Abbreviations: cmpd het = compound heterozygous; homo = homozygous; SAB = spontaneous abortions. (C) Response of the proband’s cultured fibroblasts to EPI-743 compared with inactive compound (RS-743) in the presence of oxidizing agents. The patient’s fibroblasts have increased sensitivity to oxidizing compounds, and EPI-743 rescues cell viability. (Courtesy of Edison Pharmaceuticals, Inc.) (D) Pedigree of a non-consanguineous family with multiple disorders; asterisks denote allele pairs causing disease.

Fig. 3

Newly recognized mechanisms of disease. (A) Plain radiograph of a patient showing extensive, irregular calcification and dilatation of the femoral and popliteal arteries [7]. (B) Purinergic pathway at the surface of vascular endothelial cells. Normally, CD73 (encoded by NT5E, defective in ACDC) converts adenosine monophosphate to adenosine and inorganic phosphate (Pi). Adenosine binds to the adenosine receptor, trophically inhibiting alkaline phosphatase (APL) expression. When CD73 is absent, ALP is increased and converts pyrophosphate (PPi, an inhibitor of calcification) to Pi (a stimulator of calcification). In vitro studies showed that NT5E mutant fibroblasts calcified under osteogenic conditions, and the calcification could be reversed by adenosine or an APL inhibitor. (Courtesy of Shira Ziegler, Johns Hopkins University School of Medicine.) (C) Brain MRI showing leukodystrophy in brainstem and middle cerebellar peduncles of a patient with duplication of LMNB1. (D) Log R ratios of fluorescent intensity of SNPs on chromosome 5q. A contiguous group of SNPs has higher intensity, reflecting a duplication, i.e., three total copies rather than two. The gene annotation of the region indicates that LMNB1 is encompassed by the duplication.

Fig. 4

Precision medicine: Treatment based on variant function studies. (A) Patch clamp results showing maximal response to glutamate and glycine in Xenopus oocytes transfected with the normal and mutant GRIN2A. Both the wild type and the mutant receptors were responsive to memantine inhibition. (Courtesy of Drs. Hongjie Yuan and Stephen F. Traynelis.) (B) Seizure frequency of the patient in response to various anti-epileptic medications. Note pronounced decrease in seizures on memantine. (Courtesy of Dr. Tyler Pierson.)