Bridging the Functional Gap by Synergy of Exome/Genome and RNA Sequencing: A Systematic Semi-quantitative Review Demonstrating Enhanced Diagnostic Yield in Genetic Diagnostics.

Authors

Desiree M S Tse, Wenshu Tang, Martin M C Chui, Cario W S Lo, Joe Lai, Annie T W Chu, Brian H Y Chung

Published in

Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102644. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

While exome and/or genome sequencing (ES/GS) are highly effective in identifying pathogenic variants, they may not capture the functional consequences of variants. RNA sequencing (RNA-seq), when used alongside ES/GS, addresses this limitation.
A systematic semi-quantitative review included 200 studies reporting ES/GS or that followed by RNA-seq diagnostic rates from 2014 to 2024 was conducted.
While the weighted average diagnostic rate for ES/GS followed by RNA-seq was 0.44 ranging from 0.34 to 0.53), studies with ES/GS alone reported a pooled diagnostic rate of 0.37 (95% CI: 0.35-0.39; p = 0.18). The subset of studies with ES/GS as first-tier test followed by RNA-seq revealed a trend towards improved diagnostic yields with the addition of RNA-seq (OR: 1.31, 95% CI: 1.08-1.58, p = 0.01). For participants undiagnosed by ES/GS, RNA-seq contributed an incremental diagnostic rate of 5.4% (95% CI: 0.006-0.60, p = 0.018), achieved through confirming or reclassifying candidate variants as pathogenic/likely pathogenic; and an additional diagnostic rate of 3.3% (95% CI: 0.021-0.088, p = 0.002) through discovering novel variants. Our results also highlight the advantages of tissue over blood samples in improving the diagnostic yield, particularly of RNA-seq, in which additional 6.2% for confirming ES/GS identified candidates (95% CI: 0.028-0.97, p < 0.001), and another addition of 6.2% for new variants discovery (95% CI: 0.025-0.099, p = 0.001) were found.
Our findings emphasise the synergistic value of hypothesis-driven and hypothesis-free approaches in transcriptomic data analysis. This integration of RNA-seq into ES/GS workflows has shown promise in improving molecular diagnosis of genetic diseases.

PMID:
42417141
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.

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