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Title: Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease

Abstract

Background. Despite extensive medical evaluation many patients with chronic disease remain without a diagnosis. The Undiagnosed Diseases Network (UDN) was established to embrace the most challenging cases in medicine and to characterize the biology of newly discovered diseases. Methods. The UDN was formed in 2014 as a National Institutes of Health (NIH)-funded network of seven clinical sites, two sequencing cores, and a coordinating center. Later a central biorepository, metabolomics core, and model organisms screening center were added. We undertook a retrospective evaluation of the patients referred since the network formed to evaluate the efficacy of this approach. Results. Between September 16, 2015 and May 23, 2017, 1519 patients were referred to the network (53% female). Six hundred and one cases (40%) were accepted for evaluation (53% female). Of those accepted, 192 (32%) had previously undergone exome sequencing. The most common primary symptom categories of accepted patients were neurological (40%), musculoskeletal (9.7%), immunological (6.8%), gastrointestinal (6.5%), and rheumatological (5.7%). The number of completed evaluations on May 23, 2017, was 365, at which time, 100 patients had received diagnoses. In the intervening period, a further 25 received a diagnosis indicating a network diagnosis rate of 34%. Some diagnoses were made from clinicalmore » review alone (10%). Many were informed through sequencing the exomes or genomes of the patient or family (72%). A majority of diagnoses (83%) were deemed medically actionable by the clinical team. Indeed, of the total, 30% led to changes in therapy, 24% led to changes in the diagnostic workup, and 28% allowed variant-specific genetic counseling. Through the combined work of the network, a total of 24 new syndromes were defined. Conclusions. A collaborative network with access to state-of-the-art diagnostic tools can expand the medical record of human disease providing actionable clinical diagnoses to a substantial majority of those patients.« less

Authors:
 [1];  [2];  [3];  [3];  [4];  [5];  [3];  [1];  [6];  [7];  [8];  [6];  [9];  [1];  [3];  [1];  [3];  [1]; ORCiD logo [10];  [6] more »;  [11];  [11];  [7];  [5];  [12];  [4];  [13];  [1];  [6];  [13];  [3];  [12];  [4];  [14];  [8];  [3];  [4] « less
  1. Harvard Medical School
  2. NIH Medical Center
  3. Baylor College of Medicine
  4. Stanford University
  5. University of Maryland
  6. NIH Clinical Center
  7. Vanderbilt University
  8. HudsonAlpha Institute for Biotechnology
  9. Oregon Health & Science University
  10. BATTELLE (PACIFIC NW LAB)
  11. University of California
  12. University of Oregon
  13. Duke University
  14. National Human Genome Institute
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1542071
Report Number(s):
PNNL-SA-130590
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
The New England Journal of Medicine
Additional Journal Information:
Journal Volume: 379; Journal Issue: 22
Country of Publication:
United States
Language:
English

Citation Formats

Splinter, Kimberly, Adams, David, Bacino, Carlos A., Bellen, Hugo J., Bernstein, Jon, Cheatle-Jarvela, Alys M., Eng, Christine, Esteves, Cecilia, Gahl, William, Hamid, Rizwan, Jacob, Howard, Kikani, Bijal, Koeller, David, Kohane, Isaac, Lee, Brendan H., Loscalzo, Joseph, Luo, Xi, Mccray, Alexa, Metz, Thomas O., Mulvihill, John J., Nelson, Stanley, Palmer, Christina, Phillips, John, Pick, Leslie, Postlethwait, John, Reuter, Chloe, Shashi, Vandana, Sweetser, David, Tifft, Cynthia, Walley, Nicole, Wangler, Michael, Westerfield, Monte, Wheeler, Matthew, Wise, Anastasia, Worthey, Elizabeth, Yamamoto, Shinya, and Ashley, Euan A. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. United States: N. p., 2018. Web. doi:10.1056/NEJMoa1714458.
Splinter, Kimberly, Adams, David, Bacino, Carlos A., Bellen, Hugo J., Bernstein, Jon, Cheatle-Jarvela, Alys M., Eng, Christine, Esteves, Cecilia, Gahl, William, Hamid, Rizwan, Jacob, Howard, Kikani, Bijal, Koeller, David, Kohane, Isaac, Lee, Brendan H., Loscalzo, Joseph, Luo, Xi, Mccray, Alexa, Metz, Thomas O., Mulvihill, John J., Nelson, Stanley, Palmer, Christina, Phillips, John, Pick, Leslie, Postlethwait, John, Reuter, Chloe, Shashi, Vandana, Sweetser, David, Tifft, Cynthia, Walley, Nicole, Wangler, Michael, Westerfield, Monte, Wheeler, Matthew, Wise, Anastasia, Worthey, Elizabeth, Yamamoto, Shinya, & Ashley, Euan A. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. United States. doi:10.1056/NEJMoa1714458.
Splinter, Kimberly, Adams, David, Bacino, Carlos A., Bellen, Hugo J., Bernstein, Jon, Cheatle-Jarvela, Alys M., Eng, Christine, Esteves, Cecilia, Gahl, William, Hamid, Rizwan, Jacob, Howard, Kikani, Bijal, Koeller, David, Kohane, Isaac, Lee, Brendan H., Loscalzo, Joseph, Luo, Xi, Mccray, Alexa, Metz, Thomas O., Mulvihill, John J., Nelson, Stanley, Palmer, Christina, Phillips, John, Pick, Leslie, Postlethwait, John, Reuter, Chloe, Shashi, Vandana, Sweetser, David, Tifft, Cynthia, Walley, Nicole, Wangler, Michael, Westerfield, Monte, Wheeler, Matthew, Wise, Anastasia, Worthey, Elizabeth, Yamamoto, Shinya, and Ashley, Euan A. Thu . "Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease". United States. doi:10.1056/NEJMoa1714458.
@article{osti_1542071,
title = {Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease},
author = {Splinter, Kimberly and Adams, David and Bacino, Carlos A. and Bellen, Hugo J. and Bernstein, Jon and Cheatle-Jarvela, Alys M. and Eng, Christine and Esteves, Cecilia and Gahl, William and Hamid, Rizwan and Jacob, Howard and Kikani, Bijal and Koeller, David and Kohane, Isaac and Lee, Brendan H. and Loscalzo, Joseph and Luo, Xi and Mccray, Alexa and Metz, Thomas O. and Mulvihill, John J. and Nelson, Stanley and Palmer, Christina and Phillips, John and Pick, Leslie and Postlethwait, John and Reuter, Chloe and Shashi, Vandana and Sweetser, David and Tifft, Cynthia and Walley, Nicole and Wangler, Michael and Westerfield, Monte and Wheeler, Matthew and Wise, Anastasia and Worthey, Elizabeth and Yamamoto, Shinya and Ashley, Euan A.},
abstractNote = {Background. Despite extensive medical evaluation many patients with chronic disease remain without a diagnosis. The Undiagnosed Diseases Network (UDN) was established to embrace the most challenging cases in medicine and to characterize the biology of newly discovered diseases. Methods. The UDN was formed in 2014 as a National Institutes of Health (NIH)-funded network of seven clinical sites, two sequencing cores, and a coordinating center. Later a central biorepository, metabolomics core, and model organisms screening center were added. We undertook a retrospective evaluation of the patients referred since the network formed to evaluate the efficacy of this approach. Results. Between September 16, 2015 and May 23, 2017, 1519 patients were referred to the network (53% female). Six hundred and one cases (40%) were accepted for evaluation (53% female). Of those accepted, 192 (32%) had previously undergone exome sequencing. The most common primary symptom categories of accepted patients were neurological (40%), musculoskeletal (9.7%), immunological (6.8%), gastrointestinal (6.5%), and rheumatological (5.7%). The number of completed evaluations on May 23, 2017, was 365, at which time, 100 patients had received diagnoses. In the intervening period, a further 25 received a diagnosis indicating a network diagnosis rate of 34%. Some diagnoses were made from clinical review alone (10%). Many were informed through sequencing the exomes or genomes of the patient or family (72%). A majority of diagnoses (83%) were deemed medically actionable by the clinical team. Indeed, of the total, 30% led to changes in therapy, 24% led to changes in the diagnostic workup, and 28% allowed variant-specific genetic counseling. Through the combined work of the network, a total of 24 new syndromes were defined. Conclusions. A collaborative network with access to state-of-the-art diagnostic tools can expand the medical record of human disease providing actionable clinical diagnoses to a substantial majority of those patients.},
doi = {10.1056/NEJMoa1714458},
journal = {The New England Journal of Medicine},
number = 22,
volume = 379,
place = {United States},
year = {2018},
month = {11}
}