Long-read RNA sequencing framework IsoRanker detects pathogenic non-coding variants in rare genetic conditions
Researchers developed IsoRanker, a long-read transcriptome sequencing framework that prioritizes functionally relevant variants by detecting genes and isoforms with outlier expression, allelic imbalance, or nonsense-mediated decay. The team generated paired cycloheximide-treated and untreated fibroblast transcriptomes from 31 individuals: 3 with known transcript-altering rare variants and 28 with unsolved conditions. IsoRanker recovered known transcript alterations in this cohort. Exploratory subsampling analyses suggested prioritization was largely preserved down to cohorts of 11 individuals and approximately 5 million full-length transcripts per individual. Performance depended on de novo isoform caller choice, particularly for NMD-sensitive and previously unannotated isoforms. Among 28 previously unsolved cases, IsoRanker deprioritized 8 out of 10 fibroblast-expressed candidate splice-site variants while nominating 4 new leads. In one individual, IsoRanker prioritized HARS1, revealing bi-allelic non-coding variants that together produced a partial HARS1 loss of function and informed targeted therapy in this individual.
The framework provides isoform-level functional evidence that can improve classification of non-coding variants and support diagnosis of individuals with rare genetic conditions that standard genome sequencing cannot solve.
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