Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 386, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aal5209
Keywords
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Categories
Funding
- Broad Institute's BroadIgnite program
- Broad Institute's Broadnext10 program
- NIH [GM096911, R01 HD075802, R01 AR044345, R01NS080929]
- Academy of Finland
- Finnish Cultural Foundation
- Orion-Farmos Research Foundation
- Emil Aaltonen Foundation
- Australian NHMRC (National Health and Medical Research Council)
- Australian American Association
- Muscular Dystrophy Association/American Association of Neuromuscular and Electrodiagnostic Medicine (MDA/AANEM)
- NHMRC of Australia [1080587, 1075451, 1002147, 1113531, 1022707, 1031893, 1090428]
- National Institute of General Medical Sciences (NIGMS) [F32GM115208]
- NIGMS [4T32GM007748]
- Muscular Dystrophy Association [MDA383249]
- Genome Canada
- NHMRC [APP1048816, APP1080587]
- National Human Genome Research Institute (NHGRI)
- National Eye Institute
- National Heart, Lung, and Blood Institute (NHLBI) [UM1 HG008900]
- Office of the Director of the NIH
- National Cancer Institute (NCI)
- NHGRI
- NHLBI
- National Institute on Drug Abuse (NIDA)
- National Institute of Mental Health (NIMH)
- National Institute of Neurological Disorders and Stroke (NINDS)
- NCI/Science Applications International Corporation (SAIC)-Frederick Inc. (SAIC-F) [10XS170, 10XS171]
- SAIC-F [10ST1035]
- [HHSN268201000029C]
- [DA006227]
- National Health and Medical Research Council of Australia [1080587, 1113531, 1075451, 1090428] Funding Source: NHMRC
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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 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.
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