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Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

ABSTRACT: PURPOSE: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. METHODS: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. RESULTS: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. CONCLUSION: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.

SUBMITTER: Lee H

PROVIDER: S-EPMC7405636 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

Lee Hane H Huang Alden Y AY Wang Lee-Kai LK Yoon Amanda J AJ Renteria Genecee G Eskin Ascia A Signer Rebecca H RH Dorrani Naghmeh N Nieves-Rodriguez Shirley S Wan Jijun J Douine Emilie D ED Woods Jeremy D JD Dell'Angelica Esteban C EC Fogel Brent L BL Martin Martin G MG Butte Manish J MJ Parker Neil H NH Wang Richard T RT Shieh Perry B PB Wong Derek A DA Gallant Natalie N Singh Kathryn E KE Tavyev Asher Y Jane YJ Sinsheimer Janet S JS Krakow Deborah D Loo Sandra K SK Allard Patrick P Papp Jeanette C JC Palmer Christina G S CGS Martinez-Agosto Julian A JA Nelson Stanley F SF

Genetics in medicine : official journal of the American College of Medical Genetics 20191014 3

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 31607746

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Project description:BackgroundAccording to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them.MethodsUsing data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960-2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression.ResultsDetailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2-7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07-1.45); in cases with symptom onset at age 30-44 years (OR 1.48; 95% CI 1.19-1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26-7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02-1.88).ConclusionsThis is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

Dataset Information

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

Publications

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.

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