Effect of genetic diagnosis on patients with previously undiagnosed disease

K. Splinter, D. R. Adams, C. A. Bacino, H. J. Bellen, J. A. Bernstein, A. M. Cheatle-Jarvela, C. M. Eng, C. Esteves, W. A. Gahl, R. Hamid, H. J. Jacob, B. Kikani, David Koeller, I. S. Kohane, B. H. Lee, J. Loscalzo, X. Luo, A. T. McCray, T. O. Metz, J. J. MulvihillS. F. Nelson, C. G.S. Palmer, J. A. Phillips, L. Pick, J. H. Postlethwait, C. Reuter, V. Shashi, D. A. Sweetser, C. J. Tifft, N. M. Walley, M. F. Wangler, M. Westerfield, M. T. Wheeler, A. L. Wise, E. A. Worthey, S. Yamamoto, E. A. Ashley

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Abstract

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%.

Original languageEnglish (US)
Pages (from-to)2131-2139
Number of pages9
JournalNew England Journal of Medicine
Volume379
Issue number22
DOIs
StatePublished - Nov 29 2018

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Exome
Metabolomics
Genetic Counseling
National Institutes of Health (U.S.)
Neurologic Manifestations
Health Personnel
Genome
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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Splinter, K., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., ... Ashley, E. A. (2018). Effect of genetic diagnosis on patients with previously undiagnosed disease. New England Journal of Medicine, 379(22), 2131-2139. https://doi.org/10.1056/NEJMoa1714458

Effect of genetic diagnosis on patients with previously undiagnosed disease. / Splinter, K.; Adams, D. R.; Bacino, C. A.; Bellen, H. J.; Bernstein, J. A.; Cheatle-Jarvela, A. M.; Eng, C. M.; Esteves, C.; Gahl, W. A.; Hamid, R.; Jacob, H. J.; Kikani, B.; Koeller, David; Kohane, I. S.; Lee, B. H.; Loscalzo, J.; Luo, X.; McCray, A. T.; Metz, T. O.; Mulvihill, J. J.; Nelson, S. F.; Palmer, C. G.S.; Phillips, J. A.; Pick, L.; Postlethwait, J. H.; Reuter, C.; Shashi, V.; Sweetser, D. A.; Tifft, C. J.; Walley, N. M.; Wangler, M. F.; Westerfield, M.; Wheeler, M. T.; Wise, A. L.; Worthey, E. A.; Yamamoto, S.; Ashley, E. A.

In: New England Journal of Medicine, Vol. 379, No. 22, 29.11.2018, p. 2131-2139.

Research output: Contribution to journalArticle

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, D, Kohane, IS, Lee, BH, Loscalzo, J, Luo, X, McCray, AT, Metz, TO, Mulvihill, JJ, Nelson, SF, Palmer, CGS, Phillips, JA, 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 2018, 'Effect of genetic diagnosis on patients with previously undiagnosed disease', New England Journal of Medicine, vol. 379, no. 22, pp. 2131-2139. https://doi.org/10.1056/NEJMoa1714458
Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM et al. Effect of genetic diagnosis on patients with previously undiagnosed disease. New England Journal of Medicine. 2018 Nov 29;379(22):2131-2139. https://doi.org/10.1056/NEJMoa1714458
Splinter, K. ; Adams, D. R. ; Bacino, C. A. ; Bellen, H. J. ; Bernstein, J. A. ; Cheatle-Jarvela, A. M. ; Eng, C. M. ; Esteves, C. ; Gahl, W. A. ; Hamid, R. ; Jacob, H. J. ; Kikani, B. ; Koeller, David ; Kohane, I. S. ; Lee, B. H. ; Loscalzo, J. ; Luo, X. ; McCray, A. T. ; Metz, T. O. ; Mulvihill, J. J. ; Nelson, S. F. ; Palmer, C. G.S. ; Phillips, J. A. ; Pick, L. ; Postlethwait, J. H. ; Reuter, C. ; Shashi, V. ; Sweetser, D. A. ; Tifft, C. J. ; Walley, N. M. ; Wangler, M. F. ; Westerfield, M. ; Wheeler, M. T. ; Wise, A. L. ; Worthey, E. A. ; Yamamoto, S. ; Ashley, E. A. / Effect of genetic diagnosis on patients with previously undiagnosed disease. In: New England Journal of Medicine. 2018 ; Vol. 379, No. 22. pp. 2131-2139.
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abstract = "BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35{\%}.",
author = "K. Splinter and Adams, {D. R.} and Bacino, {C. A.} and Bellen, {H. J.} and Bernstein, {J. A.} and Cheatle-Jarvela, {A. M.} and Eng, {C. M.} and C. Esteves and Gahl, {W. A.} and R. Hamid and Jacob, {H. J.} and B. Kikani and David Koeller and Kohane, {I. S.} and Lee, {B. H.} and J. Loscalzo and X. Luo and McCray, {A. T.} and Metz, {T. O.} and Mulvihill, {J. J.} and Nelson, {S. F.} and Palmer, {C. G.S.} and Phillips, {J. A.} and L. Pick and Postlethwait, {J. H.} and C. Reuter and V. Shashi and Sweetser, {D. A.} and Tifft, {C. J.} and Walley, {N. M.} and Wangler, {M. F.} and M. Westerfield and Wheeler, {M. T.} and Wise, {A. L.} and Worthey, {E. A.} and S. Yamamoto and Ashley, {E. A.}",
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T1 - Effect of genetic diagnosis on patients with previously undiagnosed disease

AU - Splinter, K.

AU - Adams, D. R.

AU - Bacino, C. A.

AU - Bellen, H. J.

AU - Bernstein, J. A.

AU - Cheatle-Jarvela, A. M.

AU - Eng, C. M.

AU - Esteves, C.

AU - Gahl, W. A.

AU - Hamid, R.

AU - Jacob, H. J.

AU - Kikani, B.

AU - Koeller, David

AU - Kohane, I. S.

AU - Lee, B. H.

AU - Loscalzo, J.

AU - Luo, X.

AU - McCray, A. T.

AU - Metz, T. O.

AU - Mulvihill, J. J.

AU - Nelson, S. F.

AU - Palmer, C. G.S.

AU - Phillips, J. A.

AU - Pick, L.

AU - Postlethwait, J. H.

AU - Reuter, C.

AU - Shashi, V.

AU - Sweetser, D. A.

AU - Tifft, C. J.

AU - Walley, N. M.

AU - Wangler, M. F.

AU - Westerfield, M.

AU - Wheeler, M. T.

AU - Wise, A. L.

AU - Worthey, E. A.

AU - Yamamoto, S.

AU - Ashley, E. A.

PY - 2018/11/29

Y1 - 2018/11/29

N2 - BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%.

AB - BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%.

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