Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.
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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 inthat 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. |
Year of Publication | 2017
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Journal | Sci Transl Med
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Volume | 9
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Issue | 386
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Date Published | 2017 Apr 19
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ISSN | 1946-6242
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DOI | 10.1126/scitranslmed.aal5209
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PubMed ID | 28424332
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PubMed Central ID | PMC5548421
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Grant list | UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01 DA006227 / DA / NIDA NIH HHS / United States
R01 AR044345 / AR / NIAMS NIH HHS / United States
R01 HD075802 / HD / NICHD NIH HHS / United States
T32 GM096911 / GM / NIGMS NIH HHS / United States
Wellcome Trust / United Kingdom
HHSN261200800001C / RC / CCR NIH HHS / United States
F32 GM115208 / GM / NIGMS NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
L60 MD010032 / MD / NIMHD NIH HHS / United States
R01 NS080929 / NS / NINDS NIH HHS / United States
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