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Improving genetic diagnosis in Mendelian disease with transcriptome sequencing
DC Field | Value | Language |
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dc.contributor.author | Cummings, Beryl B. | - |
dc.contributor.author | Marshall, Jamie L. | - |
dc.contributor.author | Tukiainen, Taru | - |
dc.contributor.author | Lek, Monkol | - |
dc.contributor.author | Donkervoort, Sandra | - |
dc.contributor.author | Foley, A. Reghan | - |
dc.contributor.author | Bolduc, Veronique | - |
dc.contributor.author | Waddell, Leigh B. | - |
dc.contributor.author | Sandaradura, Sarah A. | - |
dc.contributor.author | O'Grady, Gina L. | - |
dc.contributor.author | Estrella, Elicia | - |
dc.contributor.author | Reddy, Hemakumar M. | - |
dc.contributor.author | Zhao, Fengmei | - |
dc.contributor.author | Weisburd, Ben | - |
dc.contributor.author | Karczewski, Konrad J. | - |
dc.contributor.author | O'Donnell-Luria, Anne H. | - |
dc.contributor.author | Birnbaum, Daniel | - |
dc.contributor.author | Sarkozy, Anna | - |
dc.contributor.author | Hu, Ying | - |
dc.contributor.author | Gonorazky, Hernan | - |
dc.contributor.author | Claeys, Kristl | - |
dc.contributor.author | Joshi, Himanshu | - |
dc.contributor.author | Bournazos, Adam | - |
dc.contributor.author | Oates, Emily C. | - |
dc.contributor.author | Ghaoui, Roula | - |
dc.contributor.author | Davis, Mark R. | - |
dc.contributor.author | Laing, Nigel G. | - |
dc.contributor.author | Topf, Ana | - |
dc.contributor.author | Kang, Peter B. | - |
dc.contributor.author | Beggs, Alan H. | - |
dc.contributor.author | North, Kathryn N. | - |
dc.contributor.author | Straub, Volker | - |
dc.contributor.author | Dowling, James J. | - |
dc.contributor.author | Muntoni, Francesco | - |
dc.contributor.author | Clarke, Nigel F. | - |
dc.contributor.author | Cooper, Sandra T. | - |
dc.contributor.author | Bonnemann, Carsten G. | - |
dc.contributor.author | MacArthur, Daniel G. | - |
dc.contributor.author | GTEx Consortium | - |
dc.contributor.author | Han, Buhm | - |
dc.date.accessioned | 2023-04-25T07:33:05Z | - |
dc.date.available | 2023-04-25T07:33:05Z | - |
dc.date.created | 2023-04-21 | - |
dc.date.created | 2023-04-21 | - |
dc.date.issued | 2017-04 | - |
dc.identifier.citation | Science Translational Medicine, Vol.9 No.386, p. eaal5209 | - |
dc.identifier.issn | 1946-6234 | - |
dc.identifier.uri | https://hdl.handle.net/10371/191533 | - |
dc.description.abstract | Exome 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 COL6A 1 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. | - |
dc.language | 영어 | - |
dc.publisher | American Association for the Advancement of Science | - |
dc.title | Improving genetic diagnosis in Mendelian disease with transcriptome sequencing | - |
dc.type | Article | - |
dc.identifier.doi | 10.1126/scitranslmed.aal5209 | - |
dc.citation.journaltitle | Science Translational Medicine | - |
dc.identifier.wosid | 000399454600005 | - |
dc.identifier.scopusid | 2-s2.0-85018570855 | - |
dc.citation.number | 386 | - |
dc.citation.startpage | eaal5209 | - |
dc.citation.volume | 9 | - |
dc.description.isOpenAccess | Y | - |
dc.contributor.affiliatedAuthor | Han, Buhm | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.subject.keywordPlus | ENHANCERS ESES | - |
dc.subject.keywordPlus | RNA-SEQ | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | VARIANTS | - |
dc.subject.keywordPlus | GUIDELINES | - |
dc.subject.keywordPlus | TOOL | - |
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