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dc.contributor.authorCummings, Beryl
dc.contributor.authorMarshall, Jamie L.
dc.contributor.authorTukiainen, Taru
dc.contributor.authorLek, Monkol
dc.contributor.authorDonkervoort, Sandra
dc.contributor.authorFoley, A. Reghan
dc.contributor.authorBolduc, Veronique
dc.contributor.authorWaddell, Leigh B.
dc.contributor.authorSandaradura, Sarah A.
dc.contributor.authorO’Grady, Gina L.
dc.contributor.authorEstrella, Elicia
dc.contributor.authorReddy, Hemakumar M.
dc.contributor.authorZhao, Fengmei
dc.contributor.authorWeisburd, Ben
dc.contributor.authorKarczewski, Konrad
dc.contributor.authorO’Donnell-Luria, Anne H.
dc.contributor.authorBirnbaum, Daniel
dc.contributor.authorSarkozy, Anna
dc.contributor.authorHu, Ying
dc.contributor.authorGonorazky, Hernan
dc.contributor.authorClaeys, Kristl
dc.contributor.authorJoshi, Himanshu
dc.contributor.authorBournazos, Adam
dc.contributor.authorOates, Emily C.
dc.contributor.authorGhaoui, Roula
dc.contributor.authorDavis, Mark R.
dc.contributor.authorLaing, Nigel G.
dc.contributor.authorTopf, Ana
dc.contributor.authorKang, Peter B.
dc.contributor.authorBeggs, Alan H.
dc.contributor.authorNorth, Kathryn N.
dc.contributor.authorStraub, Volker
dc.contributor.authorDowling, James J.
dc.contributor.authorMuntoni, Francesco
dc.contributor.authorClarke, Nigel F.
dc.contributor.authorCooper, Sandra T.
dc.contributor.authorBönnemann, Carsten G.
dc.contributor.authorMacArthur, Daniel G.
dc.date.accessioned2020-10-05T20:43:06Z
dc.date.available2020-10-05T20:43:06Z
dc.date.issued2017-04
dc.date.submitted2017-01
dc.identifier.issn1946-6234
dc.identifier.issn1946-6242
dc.identifier.urihttps://hdl.handle.net/1721.1/127810
dc.description.abstractExome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches. 2017en_US
dc.description.sponsorshipNational Institutes of Health (Grant GM096911)en_US
dc.description.sponsorshipNational Institute of General Medical Sciences (Grants F32GM115208 and 4T32GM007748)en_US
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science (AAAS)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1126/scitranslmed.aal5209en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleImproving genetic diagnosis in Mendelian disease with transcriptome sequencingen_US
dc.typeArticleen_US
dc.identifier.citationCummings, Beryl B. et al. "Improving genetic diagnosis in Mendelian disease with transcriptome sequencing." Science Translational Medicine 9, 386 (April 2017): eaal5209 © 2017 The Authorsen_US
dc.contributor.departmentBroad Institute of MIT and Harvarden_US
dc.contributor.departmentLincoln Laboratoryen_US
dc.relation.journalScience Translational Medicineen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2019-06-07T14:02:30Z
dspace.date.submission2019-06-07T14:02:31Z
mit.journal.volume9en_US
mit.journal.issue386en_US


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