Diagnostic utility of transcriptome sequencing for rare Mendelian diseases



We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications.


From 234 subjects referred to the Undiagnosed Diseases Network, University of California–Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide.


The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality.


In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.

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Supported by awards from the National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination and the Office of the NIH Director: U01HG007703 to the University of California–Los Angeles, U01HG007942 to Baylor College of Medicine, and U01HG007943 to HudsonAlpha Institute for Biotechnology. J.D.W. is supported by the UCLA Intercampus Medical Genetics Training Program, US Department of Health and Human Services (USHHS) Ruth L. Kirschstein Institutional National Research Service Award T32GM008243. This research and cores used are supported by NIH National Center for Advancing Translational Science (NCATS) UCLA Clinical and Translational Science Institute (CTSI) grant number UL1TR001881. B.L.F. is supported by NIH R01NS082094. S.N.-R. is supported by the NIH Training Grant in Genomic Analysis and Interpretation T32HG002536.

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Correspondence to Stanley F. Nelson MD.

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Lee, H., Huang, A.Y., Wang, L. et al. Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genet Med (2019). https://doi.org/10.1038/s41436-019-0672-1

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  • transcriptome sequencing
  • genome sequencing
  • exome sequencing
  • undiagnosed rare Mendelian diseases
  • molecular diagnosis

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