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Stanford Center for Undiagnosed Diseases Network Resources

"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."

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Diagnoses from the Stanford Team

De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck , Emily G. Farrow,, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie , Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sebastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Undiagnosed Diseases Network, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, HsiaoTuan Chao. Am J Hum Genet. 2020 Apr 2;106(4):570-583. PMID:32197074 Full text

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Ghayda Mirzaa, M.D., Jessica X. Chong, Ph.D., Amélie Piton, M.D., Bernt Popp, M.D., Kimberly Foss, M.S., Hui Guo, Ph.D., Ricardo Harripaul, M.Sc., Kun Xia, Ph.D., Joshua Scheck, B.S., Kimberly A. Aldinger, Ph.D., Samin A. Sajan, Ph.D., Sha Tang, Ph.D., Dominique Bonneau, M.D., Ph.D., Anita Beck, M.D., Ph.D., Janson White, Ph.D., Sonal Mahida, M.G.C., C.G.C., Jacqueline Harris, M.D., Constance Smith-Hicks, M.D., Ph.D., Juliane Hoyer, M.D., Christiane Zweier, M.D., Ph.D., André Reis, M.D., Christian T. Thiel, M.D., Rami Abou Jamra, M.D., Natasha Zeid, M.S., C.G.C., Amy Yang, M.D., Laura S. Farach, M.D., Laurence Walsh, M.D., Katelyn Payne, M.S., C.G.C., Luis Rohena, M.D., Milen Velinov, M.D., Ph.D., Alban Ziegler, M.D., Elise Schaefer, M.D., Ph.D., Vincent Gatinois, M.D., Ph.D.,, David Geneviève, M.D., Ph.D.,, Marleen E.H. Simon, M.D., Jennefer Kohler, M.S., Joshua Rotenberg, M.D., Patricia Wheeler, M.D., Austin Larson, M.D., Michelle E. Ernst, M.S., C.G.C., Cigdem I. Akman, M.D., Rachel Westman, M.S., C.G.C, Patricia Blanchet, M.D., Lori-Anne Schillaci, M.D., Catherine Vincent-Delorme, M.D., Karen W. Gripp, M.D., Francesca Mattioli, Ph.D., Gwenaël Le Guyader, M.D., Ph.D., Bénédicte Gerard, M.D., Michèle Mathieu-Dramard, M.D., Gilles Morin, M.D., Roksana Sasanfar, M.D., Muhammad Ayub, M.D., Nasim Vasli, Ph.D., Sandra Yang, M.S., C.G.C., Rick Person, Ph.D., Kristin G. Monaghan, Ph.D., Deborah A. Nickerson, Ph.D., Ellen van Binsbergen, M.D., Gregory M Enns, M.B.Ch.B., Annika M Dries, B.S., Leah J Rowe, M.S., C.G.C., Anne CH Tsai, M.D., Shayna Svihovec, M.S., C.G.C., Jennifer Friedman, M.D., Zehra Agha, M.D., Raheel Qamar, M.D., Lance H. Rodan, M.D., Julian Martinez-Agosto, M.D., Ph.D., Charlotte W. Ockeloen, M.D., Marie Vincent, M.D., William James Sunderland, Ph.D., Jonathan A. Bernstein, M.D., Ph.D., Undiagnosed Diseases Network, Evan E. Eichler, Ph.D., John B. Vincent, Ph.D., University of Washington Center for Mendelian Genomics (UW-CMG), and Michael J. Bamshad, M.D. Genet Med. 2020 Mar; 22(3): 538–546. PMID: 31723249 Full text

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases

Perenthaler E, Nikoncuk A, Yousefi S, Berdowski WM, Alsagob M, Capo I, van der Linde HC, van den Berg P, Jacobs EH, Putar D, Ghazvini M, Aronica E, van IJcken WFJ, de Valk WG, Medici-van den Herik E, van Slegtenhorst M, Brick L, Kozenko M, Kohler JN, Bernstein JA, Monaghan KG, Begtrup A, Torene R, Al Futaisi A, Al Murshedi F, Mani R, Al Azri F, Kamsteeg EJ, Mojarrad M, Eslahi A, Khazaei Z, Darmiyan FM, Doosti M, Karimiani EG, Vandrovcova J, Zafar F, Rana N, Kandaswamy KK, Hertecant J, Bauer P, AlMuhaizea MA, Salih MA, Aldosary M, Almass R, Al-Quait L, Qubbaj W, Coskun S, Alahmadi KO, Hamad MHA, Alwadaee S, Awartani K, Dababo AM, Almohanna F, Colak D, Dehghani M, Mehrjardi MYV, Gunel M, Ercan-Sencicek AG, Passi GR, Cheema HA, Efthymiou S, Houlden H, Bertoli-Avella AM, Brooks AS, Retterer K, Maroofian R, Kaya N, van Ham TJ, Barakat TS. Acta Neuropathol.2019 Dec 9. PMID:31820119 Full text

Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review

Kumar A, Zastrow DB, Kravets EJ, Beleford D, Ruzhnikov MRZ, Grove ME, Dries AM, KohlerJN, Waggott DM, Yang Y, Huang Y; Undiagnosed Diseases Network, Mackenzie KM, Eng CM, Fisher PG, Ashley EA, Teng JM, Stevenson DA, Shieh JT, Wheeler MT, Bernstein JA. Am J Med Genet A. 2019 Jun;179(6):966-977. PMID:30920161 Full text

Genotype-phenotype correlations in individuals with pathogenic RERE variants

Valerie K. Jordan, Brieana Fregeau, Xiaoyan Ge, Jessica Giordano, Ronald J. Wapner, Tugce B. Balci, Melissa T. Carter, John A. Bernat, Amanda N. Moccia, Anshika Srivastava, Donna M. Martin, Stephanie L. Bielas, John Pappas, Melissa D. Svoboda, Marlène Rio, Nathalie Boddaert, Vincent Cantagrel, Andrea M. Lewis,, Fernando Scaglia, Undiagnosed Diseases Network, Jennefer N. Kohler, Jonathan A. Bernstein, Annika M. Dries, Jill A. Rosenfeld, Colette DeFilippo, Willa Thorson, Yaping Yang, Elliott H. Sherr, Weimin Bi, and Daryl A. Scott. Hum Mutat. 2018 May; 39(5): 666–675. PMID:29330883 Full text

Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder

Monika Oláhová, Wan Hee Yoon, Kyle Thompson, Sharayu Jangam, Liliana Fernandez, Jean M. Davidson, Jennifer E. Kyle, Megan E. Grove, Dianna G. Fisk, Jennefer N. Kohler, Matthew Holmes, Annika M. Dries, Yong Huang, Chunli Zhao, Kévin Contrepois, Zachary Zappala, Laure Frésard, Daryl Waggott, Erika M. Zink, Young-Mo Kim, Heino M. Heyman, Kelly G. Stratton, Bobbie-Jo M. Webb-Robertson, Undiagnosed Diseases Network, Michael Snyder, Jason D. Merker, Stephen B. Montgomery, Paul G. Fisher, René G. Feichtinger, Johannes A. Mayr, Julie Hall, Ines A. Barbosa, Michael A. Simpson, Charu Deshpande, Katrina M. Waters, David M. Koeller, Thomas O. Metz, Andrew A. Morris, Susan Schelley, Tina Cowan, Marisa W. Friederich, Robert McFarland, Johan L.K. Van Hove, Gregory M. Enns, Shinya Yamamoto, Euan A. Ashley, Michael F. Wangler, Robert W. Taylor, Hugo J. Bellen, Jonathan A. Bernstein, and Matthew T. Wheeler. Am J Hum Genet. 2018 Mar 1; 102(3): 494–504. PMID:29478781 Full text

Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype

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. Cold Spring Harbor Molecular Case Studies. 2017 Jan; 3(1) a001388. Full text

Featured Papers on the Undiagnosed Diseases Network

Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing

Reuter CM, Kohler JN, Bonner D, Zastrow D, Fernandez L, Dries A, Marwaha S, Davidson J, Brokamp E, Herzog M, Hong J, Macnamara E, Rosenfeld JA, Schoch K, Spillmann R; UndiagnosedDiseases Network, Loscalzo J, Krier J, Stoler J, Sweetser D, Palmer CGS, Phillips JA, Shashi V, Adams DA, Yang Y, Ashley EA, Fisher PG, Mulvihill JJ, Bernstein JA, Wheeler MT. J Genet Couns.2019 Dec;28(6):1107-1118. PMID:31478310 Full text

ClinPhen extracts and prioritizes patient phenotypes directly from medical records to expedite genetic disease diagnosis

Deisseroth CA, Birgmeier J, Bodle EE, Kohler JN, Matalon DR, Nazarenko Y, Genetti CA, Brownstein CA, Schmitz-Abe K, Schoch K, Cope H, Signer R; Undiagnosed Diseases Network, Martinez-Agosto JA, Shashi V, Beggs AH, Wheeler MT, Bernstein JA, Bejerano G. Genet Med.2019 Jul;21(7):1585-1593. PMID:30514889 Full text

Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts

Frésard L, Smail C, Ferraro NM, Teran NA, Li X, Smith KS, Bonner D, Kernohan KD, Marwaha S, Zappala Z, Balliu B, Davis JR, Liu B, Prybol CJ, Kohler JN, Zastrow DB, Reuter CM, Fisk DG, Grove ME, Davidson JM, Hartley T, Joshi R, Strober BJ, Utiramerur S; Undiagnosed Diseases Network; CareRare Canada Consortium, Lind L, Ingelsson E, Battle A, Bejerano G, Bernstein JA, Ashley EA, Boycott KM, Merker JD, Wheeler MT, Montgomery SB. Nat Med.2019 Jun;25(6):911-919. PMID:31160820 Full text

A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing

Zastrow DB, Kohler JN, Bonner D, Reuter CM, Fernandez L, Grove ME, Fisk DG; Undiagnosed Diseases Network, Yang Y, Eng CM, Ward PA, Bick D, Worthey EA, Fisher PG, Ashley EA, Bernstein JA, Wheeler MT. J Genet Couns. 2019;28:213-228. PMID:30964584 Full text

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA 3rd, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA; Undiagnosed Diseases Network. N Engl J Med.2018 Nov 29;379(22):2131-2139. PMID:30304647 Full text

A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network

Reuter CM, Brimble E, DeFilippo C, Dries AM, Undiagnosed Diseases Network, Enns GM, Ashley EA, Bernstein JA, Fisher PG, Wheeler MT. J Pediatr. 2018 Jan 11. pii: S0022-3476(17)31723-7. Full text

Long-read genome sequencing identifies causal structural variation in a Mendelian disease

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. Genet Med. 2018 Jan;20(1): 159-163. Full text

The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease

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. Am J Hum Genet. 2017 Feb 2;100(2):185-192. Full text

The Undiagnosed Diseases Network of the National Institutes of Health: A National Extension

Gahl WA, Wise AL, Ashley, EA. JAMA. 2015 Nov 3;314(17):1797-1798. Full text

The NIH Undiagnosed Diseases Program: lessons learned

Gahl WA, Tifft CJ. JAMA. 2011 May 11;305(18):1904-5. doi: 10.1001/jama.2011.613. Full text

Other Selected Works

2016

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

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. Molecular genetics and metabolism 117.4 (2016): 393-400.

2015

Data Sharing in the Undiagnosed Diseases Network

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

2014

Clinical Interpretation and Implications of Whole-Genome Sequencing

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

Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway

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. Genetics in Medicine. 2014 Oct;16 Full text

2012

The NIH Undiagnosed Diseases Program: bonding scientists and clinicians

Gahl WA, Boerkoel CF, Boehm M. Dis Model Mech. 2012 Jan;5(1):3-5. doi: 10.1242/dmm.009258. Full text

2011

Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence

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. PLOS Genetics. 2011 Sept;15. Full text

The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases

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. Genet Med. 2012 Jan;14(1):51-9. doi: 10.1038/gim.0b013e318232a005. Epub 2011 Sep 26. Full text

Photography credit: Mark Tuschman 2009