Long-read transcriptome analysis using IsoRanker for identifying pathogenic variants in Mendelian conditions.

IsoRanker identifies pathogenic variants in Mendelian conditions with high accuracy using long-read transcriptome sequencing, even in small cohorts of around 11 individuals.

• Why it matters: Detecting functional non-coding variants in Mendelian diseases is difficult due to limited understanding of their impact on gene function, hindering diagnosis and treatment.
• What they did: The study applied IsoRanker to paired fibroblast transcriptomes from 31 individuals, analyzing gene and isoform expression, allelic imbalance, and NMD effects, with a focus on known and unknown variants.
• The result: IsoRanker successfully recovered known transcript alterations, prioritized new pathogenic candidates, and revealed bi-allelic non-coding variants in HARS1, aiding diagnosis and targeted therapy development.