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Improving genetic diagnosis in Mendelian disease with transcriptome sequencing

Cummings, BB; Marshall, JL; Tukiainen, T; Lek, M; Donkervoort, S; Foley, AR; Bolduc, V; ... MacArthur, DG; + view all (2017) Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Science Translational Medicine , 9 (386) 10.1126/scitranslmed.aa15209. Green open access

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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 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.

Type: Article
Title: Improving genetic diagnosis in Mendelian disease with transcriptome sequencing
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.aa15209
Publisher version: https://doi.org/10.1126/scitranslmed.aa15209
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, NEUROMUSCULAR DISEASES, MUSCULAR-DYSTROPHIES, SPLICING SIGNALS, ENHANCERS ESES, RNA-SEQ, VARIANTS, MUTATIONS, OPPORTUNITIES, CHALLENGES, PREDICTION
URI: http://discovery.ucl.ac.uk/id/eprint/10055859
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