Targeted reflex RNA sequencing for enhanced variant classification on exome and genome sequencing improves patient outcomes.

Targeted reflex RNA-seq from peripheral blood RNA for functional evaluation of splicing variants identified by ES/GS

A prospective clinical study evaluates targeted reflex RNA-seq as a complement to exome and genome sequencing for splicing variant classification. Among 131 patients with predicted splicing variants, 64 underwent RNA-seq: 42.2% of VUS were reclassified, with clinical management changes in 71% and therapeutic modifications in 43% of positive cases. The approach uses peripheral blood RNA, requiring no additional biopsy. The authors provide a decision tree for RNA-seq candidate selection.

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Reflex RNA-seq is no longer a research option—this study demonstrates direct, measurable clinical utility with concrete impact criteria. The use of peripheral blood RNA greatly simplifies implementation, although transcript expression may remain insufficient for certain tissue-specific genes.

Clinical impact: 3/3 · Evidence strength: 3/3 · Novelty: 1/2 · Sample size: 1/1 · Publication status: 1/1 → Total: 9/10