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Tytuł:
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Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test.
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Autorzy:
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Brockman DG; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. .; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. .
Austin-Tse CA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Pelletier RC; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Harley C; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Patterson C; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Head H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Leonard CE; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
O'Brien K; Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.
Mahanta LM; Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.
Lebo MS; Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA.
Lu CY; Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.
Natarajan P; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Khera AV; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Aragam KG; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Kathiresan S; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Rehm HL; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Udler MS; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
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Źródło:
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Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Sep; Vol. 23 (9), pp. 1689-1696. Date of Electronic Publication: 2021 May 11.
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Typ publikacji:
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Journal Article; Randomized Controlled Trial; Research Support, N.I.H., Extramural
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Język:
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English
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Imprint Name(s):
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Publication: 2022- : [New York] : Elsevier
Original Publication: Baltimore, MD : Lippincott, Williams & Wilkins, c1998-
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MeSH Terms:
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Genetic Testing*
Pathology, Molecular*
Adult ; Child ; Chromosome Mapping ; Humans ; Molecular Diagnostic Techniques ; Prospective Studies
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References:
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Grant Information:
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K23 DK114551 United States DK NIDDK NIH HHS; R01 HG010372 United States HG NHGRI NIH HHS
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Entry Date(s):
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Date Created: 20210512 Date Completed: 20211018 Latest Revision: 20240403
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Update Code:
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20240403
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PubMed Central ID:
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PMC8488861
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DOI:
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10.1038/s41436-021-01193-y
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PMID:
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33976420
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Purpose: To evaluate the diagnostic yield and clinical relevance of clinical genome sequencing (cGS) as a first genetic test for patients with suspected monogenic disorders.
Methods: We conducted a prospective randomized study with pediatric and adult patients recruited from genetics clinics at Massachusetts General Hospital who were undergoing planned genetic testing. Participants were randomized into two groups: standard-of-care genetic testing (SOC) only or SOC and cGS.
Results: Two hundred four participants were enrolled, 202 were randomized to one of the intervention arms, and 99 received cGS. In total, cGS returned 16 molecular diagnoses that fully or partially explained the indication for testing in 16 individuals (16.2% of the cohort, 95% confidence interval [CI] 8.9-23.4%), which was not significantly different from SOC (18.2%, 95% CI 10.6-25.8%, P = 0.71). An additional eight molecular diagnoses reported by cGS had uncertain relevance to the participant's phenotype. Nevertheless, referring providers considered 20/24 total cGS molecular diagnoses (83%) to be explanatory for clinical features or worthy of additional workup.
Conclusion: cGS is technically suitable as a first genetic test. In our cohort, diagnostic yield was not significantly different from SOC. Further studies addressing other variant types and implementation challenges are needed to support feasibility and utility of broad-scale cGS adoption.
(© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)
