1. Diagnostic utility of transcriptome sequencing for rare Mendelian diseases
- Author
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Lee, Hane, Huang, Alden Y, Wang, Lee-Kai, Yoon, Amanda J, Renteria, Genecee, Eskin, Ascia, Signer, Rebecca H, Dorrani, Naghmeh, Nieves-Rodriguez, Shirley, Wan, Jijun, Douine, Emilie D, Woods, Jeremy D, Dell'Angelica, Esteban C, Fogel, Brent L, Martin, Martin G, Butte, Manish J, Parker, Neil H, Wang, Richard T, Shieh, Perry B, Wong, Derek A, Gallant, Natalie, Singh, Kathryn E, Tavyev Asher, Y Jane, Sinsheimer, Janet S, Krakow, Deborah, Loo, Sandra K, Allard, Patrick, Papp, Jeanette C, Undiagnosed Diseases Network, Palmer, Christina GS, Martinez-Agosto, Julian A, and Nelson, Stanley F
- Subjects
Clinical Sciences ,transcriptome sequencing ,Whole Exome Sequencing ,Rare Diseases ,Clinical Research ,undiagnosed rare Mendelian diseases ,Exome Sequencing ,molecular diagnosis ,Pathology ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Exome ,Genetic Testing ,RNA-Seq ,Aetiology ,Genetics & Heredity ,screening and diagnosis ,Whole Genome Sequencing ,Prevention ,Human Genome ,Molecular ,Undiagnosed Diseases Network ,DNA ,4.1 Discovery and preclinical testing of markers and technologies ,genome sequencing ,Detection ,Inborn ,Good Health and Well Being ,Genetic Diseases ,Mutation ,Transcriptome ,Sequence Analysis - Abstract
PurposeWe 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.MethodsFrom 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.ResultsThe 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.ConclusionIn 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.
- Published
- 2020