Language
English
Publication Date
6-5-2026
Journal
npj Genomic Medicine
DOI
10.1038/s41525-026-00571-2
PMID
42248868
Abstract
RNA sequencing (RNA-seq) has been utilized to provide functional evidence regarding the impact of splicing variants. This study explores the utility of targeted reflex RNA-seq to inform classification of predicted splicing variants identified through clinical exome sequencing (ES) and genome sequencing (GS). A retrospective analysis was conducted on consecutive ES/GS cases completed at a single center in which targeted reflex RNA-seq was performed following identification of eligible variants. There were 131 cases (4.1%) that had at least one RNA-seq eligible variant reported, with eight of these cases having two unique eligible variants. Of the 139 eligible variants, 125 were classified as variants of uncertain significance (VUS). Sixty-four cases had targeted reflex RNA-seq completed with 27 cases having at least one variant reclassified (42.2%). After reclassification, 23 cases had positive results, and two cases had a likely diagnosis of an autosomal recessive condition. Clinical outcomes data regarding positive RNA-seq cases showed that 71% (10/14) had clinical management changes and 43% (6/14) had treatment changes. Incorporation of targeted reflex RNA-seq analysis into the diagnostic pipeline of rare diseases enhances variant classification and resolves uncertainty regarding predicted splice variants, leading to an estimated 1.6% increase in diagnostic yield of clinical ES/GS.
Published Open-Access
yes
Recommended Citation
Zhao, Xiaonan; Rigobello, Robert; Driver, Morgan; et al., "Targeted Reflex RNA Sequencing for Enhanced Variant Classification on Exome and Genome Sequencing Improves Patient Outcomes" (2026). Faculty, Staff and Students Publications. 7099.
https://digitalcommons.library.tmc.edu/baylor_docs/7099