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N Engl J Med. 2018 Nov 29;379(22):2131-2139. doi: 10.1056/NEJMoa1714458. Epub 2018 Oct 10.

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

Collaborators (148)

Alejandro ME, Allard P, Azamian MS, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Bican A, Bick DP, Birch CL, Bonner D, Boone BE, Bostwick BL, Briere LC, Brown DM, Brush M, Burke EA, Burrage LC, Chen S, Clark GD, Coakley TR, Cogan JD, Cooper CM, Cope H, Craigen WJ, D’Souza P, Davids M, Davidson JM, Dayal JG, Dell’Angelica EC, Dhar SU, Dillon A, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Dries AM, Eckstein DJ, Emrick LT, Enns GM, Eskin A, Estwick T, Fernandez L, Fisher PG, Fogel BL, Friedman ND, Glanton E, Godfrey RA, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hanchard NA, Handley LH, Herzog MR, Holm IA, Hom J, Howerton EM, Jain M, Jiang YH, Johnston JM, Jones AL, Kohler JN, Krasnewich DM, Krieg EL, Krier JB, Kyle JE, Lalani SR, Lau CC, Lazar J, Lee H, Levy SE, Lewis RA, Lincoln SA, Lipson A, Loo SK, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Marttnez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, Merker JD, Might M, Moretti PM, Murphy JL, Muzny DM, Nehrebecky ME, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Pallais JC, Papp JC, Parker NH, Pena LDM, Posey JE, Potocki L, Pusey BN, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Schroeder MC, Scott DA, Sharma P, Silverman EK, Sinsheimer JS, Smith KS, Soldatos AG, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Toro C, Tran AA, Urv TK, Valivullah ZM, Vilain E, Vogel TP, Waggott DM, Wahl CE, Walsh CA, Ward PA, Waters KM, Webb-Robertson BM, Wolfe LA, Yang Y, Yu G, Zastrow DB, Zhao C, Zheng A.

Author information

From Harvard Medical School (K.S., C.E., I.S.K., J.L., A.T.M., D.A.S.), Brigham and Women's Hospital (J.L.), and Massachusetts General Hospital (D.A.S.) - all in Boston; the National Institutes of Health Clinical Center (D.R.A., W.A.G., J.J.M., C.J.T.) and the National Human Genome Research Institute (A.L.W.), Bethesda, and the University of Maryland, College Park (A.M.C.-J., B.K., L.P.) - all in Maryland; Baylor College of Medicine, Houston (C.A.B., H.J.B., C.M.E., B.H.L., X.L., M.F.W., S.Y.); Stanford University, Stanford (J.A.B., C.R., M.T.W., E.A.A.), and the University of California, Los Angeles, Los Angeles (S.F.N., C.G.S.P.) - both in California; Vanderbilt University, Nashville (R.H., J.A.P.); HudsonAlpha Institute for Biotechnology, Huntsville, AL (H.J.J., E.A.W.); Oregon Health and Science University, Portland (D.M.K.); the Pacific Northwest National Laboratory, Richland, WA (T.O.M.); the University of Oregon, Eugene (J.H.P., M.W.); and Duke University, Durham, NC (V.S., N.M.W.).



Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.


We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.


A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.


The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

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