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"The UDN, based on a pilot program launched in 2008 at the NIH Clinical Center in Bethesda, Maryland, is developing approaches for the diagnosis of difficult-to-solve medical cases. Along with traditional methods, doctors pursue medical diagnoses for patients by analyzing DNA sequence, which can reveal variants in patients' genome that may be the cause of a disease. Genome sequencing is an increasingly fast and inexpensive technology that only recently has been used for patient diagnosis.

Genome sequencing for patients from the NIH Undiagnosed Diseases Program (UDP) has identified individual variation in genes that clinical researchers want to understand better, especially how their function or malfunction may affect a disease condition. Investigation of gene function is a critical step in the process leading to diagnoses and potential treatments for patients with these rare or new diseases." full article here

PODCAST: Euan Ashley on harnessing the power of genomics.

Breaking Diagnoses from the Stanford Team: 

Zastrow, Diane B, Zornio, Patricia A, Dries, Annika, Kohler, Jennifer, Fernandez, Liliana, Waggott, Daryl, Walkiewicz, Magdelina, Eng, Christine M, Manning, A Melanie, Farrelly, Ellen, Members Undiagnosed Diseases Network, Fisher, Paul G, Ashley, Euan A, Bernstein, Jonathan A, Wheeler, Matthew T. "Exome Sequencing Identifies De Novo Pathogenic Variants in FBN1 and TRPS1 in a Patient with a Complex Connective Tissue Phenotype." Molecular Case Studies (2016): mcs. a001388.

Featured Papers on the Undiagnosed Diseases Network: 

Oláhová M, Yoon WH, Thompson K, Jangam S, Fernandez L, Davidson JM, Kyle JE, Grove ME, Fisk DG, Kohler JN, Holmes M, Dries AM, Huang Y, Zhao C, Contrepois K, Zappala Z, Frésard L, Waggott D, Zink EM, Kim YM, Heyman HM, Stratton KG, Webb-Robertson BM, Undiagnosed Diseases Network, Synder M, Merker JD, Montgomery SB, Fisher PG, Feichtinger RG, Mayr JA, Hall J, Barbosa IA, Simpson MA, Deshpande C, Waters KM, Koeller DM, Koeller DM, Koeller DM, Metz TO, Morris AA, Schelley S, Cowan T, Friederich MW, McFarland R, Van Hove JLK, Enns GM, Yamamoto S, Ashley EA, Wanger MF, Taylor RW, Bellen HJ, Bernstein JA, Wheeler MT. Bialllelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Am J Hum Genet. 2018 Mar 1; 102(3):494-504. full text

Reuter CM, Brimble E, DeFilippo C, Dries AM, Undiagnosed Diseases Network, Enns GM, Ashley EA, Bernstein JA, Fisher PG, Wheeler MT. A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network. J Pediatr. 2018 Jan 11. pii: S0022-3476(17)31723-7. full text

Jordan VK, Fregeau B, Ge X, Giordano J, Wapner RJ, Balci TB, Carter MT, Bernat JA, Moccia AN, Srivastava A, Martin DM, Bielas SL, Pappas J, Svoboda MD, Rio M, Boddaert N, Cantagrel V, Lewis AM, Scaglia F; Undiagnosed Diseases Network, Kohler JN, Bernstein JA, Dries AM, Rosenfeld JA, DeFilippo C, Thorson W, Yang Y, Sherr EH, Bi W, Scott DA. Genotype-phenotype correlations in individuals with pathogenic RERE variants. Human Mutation 2018, 39(5), 666–675. full text

Merker JD, Wenger AM, Sneddon T, Grove M, Zappala Z, Fresard L, Waggott D, Utiramerur S, Hou Y, Smith KS, Montgomery SB, Wheeler M, Buchan JG, Lambert CC, Eng KS, Hickey L, Korlach J, Ford J, Ashley EA. Long-read genome sequencing identifies causal structural variation in a Mendelian disease. Genet Med. 2018 Jan;20(1): 159-163. full text

Ramoni RB, Mulvihill JJ, Adams DR, Allard P, Ashley EA, Bernstein JA, Gahl WA, Hamid R, Loscalzo J, McCray AT, Shashi V, Tifft CJ; Undiagnosed Diseases Network, Wise AL. The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease. Am J Hum Genet. 2017 Feb 2;100(2):185-192. full text

Zastrow DB, Zornio PA, Dries A, Kohler J, Fernandez L, Waggott D, Walkiewicz M, Eng CM, Manning MA, Farrelly E, Fisher PG, Ashley EA, Bernstein JA, Wheeler MT. Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype. Cold Spring Harbor Molecular Case Studies. 2017 Jan; 3(1) a001388. full text

Gahl WA, Wise AL, Ashley, EA. The Undiagnosed Diseases Network of the National Institutes of Health: A National Extension. JAMA. 2015 Nov 3;314(17):1797-1798. full text

Gahl WA, Tifft CJ. The NIH Undiagnosed Diseases Program: lessons learned. JAMA. 2011 May 11;305(18):1904-5. doi: 10.1001/jama.2011.613. full text

In the News

Other Selected Works:


Gahl, William A, Mulvihill, John J, Toro, Camilo, Markello, Thomas C, Wise, Anastasia L, Ramoni, Rachel B, Adams, David R, Tifft, Cynthia J, and Members of the UDN. "The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine." Molecular genetics and metabolism 117.4 (2016): 393-400.


Brownstein, Catherine A, Holm, Ingrid A, Ramoni, Rachel, Goldstein, David B, and Members of the Undiagnosed Diseases Network. "Data Sharing in the Undiagnosed Diseases Network." Human mutation 36.10 (2015): 985-988.


Frederick E. Dewey, MD1,2,3,4; Megan E. Grove, MS1,2,3,4; Cuiping Pan, PhD4,5; Benjamin A. Goldstein, PhD6; Jonathan A. Bernstein, MD, PhD7; Hassan Chaib, PhD4,5; Jason D. Merker, MD, PhD8; Rachel L. Goldfeder, BS9; Gregory M. Enns, MB, ChB7; Sean P. David, MD, DPhil6; Neda Pakdaman, MD6; Kelly E. Ormond, MS5,10; Colleen Caleshu, MS1,2,3,7; Kerry Kingham, MS11; Teri E. Klein, PhD5; Michelle Whirl-Carrillo, PhD5; Kenneth Sakamoto, MD3,6; Matthew T. Wheeler, MD, PhD1,2,3,4; Atul J. Butte, MD, PhD7,12; James M. Ford, MD, PhD11; Linda Boxer, MD6; John P. A. Ioannidis, MD, PhD6,12,14,15; Alan C. Yeung, MD2,3; Russ B. Altman, MD, PhD5,6,16; Themistocles L. Assimes, MD, PhD2,3; Michael Snyder, PhD2,4,5; Euan A. Ashley, MRCP, DPhil1,2,3,4,5; Thomas Quertermous, MD1,2,3,4. JAMA. 2014 Mar;12 full text Gregory M. Enns, MB, ChB,1,* Vandana Shashi, MD, MBBS,2,* Matthew Bainbridge, PhD,3,* Michael J. Gambello, MD, PhD,4 Farah R. Zahir, PhD,5 Thomas Bast, MD,6 Rebecca Crimian, MS,2 Kelly Schoch, MS,2 Julia Platt, MS,1 Rachel Cox, MS,1 Jonathan Bernstein, MD, PhD,1 Mena Scavina, DO,7 Rhonda S. Walter, MD,8 Audrey Bibb, MS,4 Melanie Jones, PhD,4 Madhuri Hegde, PhD,4 Brett H. Graham, MD, PhD,3 Anna C. Need, PhD,9 Angelica Oviedo, MD,10 Christian P. Schaaf, MD, PhD,3,11 Sean Boyle, PhD,12 Atul J. Butte, MD, PhD,12 Rong Chen, PhD,12 Michael J. Clark, PhD,12 Rajini Haraksingh, PhD,12 Tina M. Cowan, PhD,13 FORGE Canada Consortium,14 Ping He, MD, PhD,15 Sylvie Langlois, MD,5 Huda Y. Zoghbi, MD,3,11,16 Michael Snyder, PhD,12 Richard Gibbs, PhD,3 Hudson H. Freeze, PhD,15 and David B. Goldstein, PhD17,18. Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway. Genetics in Medicine. 2014 Oct;16 full text


Gahl WA, Boerkoel CF, Boehm M. The NIH Undiagnosed Diseases Program: bonding scientists and clinicians. Dis Model Mech. 2012 Jan;5(1):3-5. doi: 10.1242/dmm.009258. full text


Frederick E. Dewey, Rong Chen, Sergio P. Cordero, Kelly E. Ormond, Colleen Caleshu, Konrad J. Karczewski, Michelle Whirl-Carrillo, Matthew T. Wheeler, Joel T. Dudley, Jake K. Byrnes, Omar E. Cornejo, Joshua W. Knowles, Mark Woon, Katrin Sangkuhl, Li Gong, Caroline F. Thorn, Joan M. Hebert, Emidio Capriotti, Sean P. David, Aleksandra Pavlovic, Anne West, Joseph V. Thakuria, Madeleine P. Ball, Alexander W. Zaranek, Heidi L. Rehm, George M. Church, John S. West, Carlos D. Bustamante, Michael Snyder, Russ B. Altman, Teri E. Klein, Atul J. Butte, Euan A. Ashley. Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence. PLOS Genetics. 2011 Sept;15. full text Gahl WA, Markello TC, Toro C, Fajardo KF, Sincan M, Gill F, Carlson-Donohoe H, Gropman A, Pierson TM, Golas G, Wolfe L, Groden C, Godfrey R, Nehrebecky M, Wahl C, Landis DM, Yang S, Madeo A, Mullikin JC, Boerkoel CF, Tifft CJ, Adams D. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med. 2012 Jan;14(1):51-9. doi: 10.1038/gim.0b013e318232a005. Epub 2011 Sep 26. full text Photography credit: Mark Tuschman 2009