A reproducible transcriptomic signature supports interpretation of metatranscript-only TTN variants in recessive titinopathy

Titinopathies are neuromuscular disorders caused by defect in TTN and are difficult to diagnose because of variable clinical presentation and frequent detection of TTN variants in asymptomatic individuals. An autosomal-recessive subtype that has only recently been delineated involves one or both pathogenic variants located within the metatranscript-only exons, outside canonical skeletal or cardiac isoforms. Affected individuals present with mild, early-onset contractures and/or myopathy that stabilizes or improves with age; however, no distinct omics features have been reported to differentiate this subtype from other neuromuscular disorders or unaffected individuals. We describe four previously unreported families with recessive titinopathy, three of which represent this subtype. Muscle transcriptome analysis revealed preserved overall TTN expression but a consistent regional isoform shift within the I-band, characterised by reduced inclusion of metatranscript-only exons across the PEVK region. This shift was confirmed by orthogonal assays, reproduced in an independently identified patient, and showed strong discrimination in combined-cohort analyses. These findings identify a reproducible transcriptomic signature that may provide supportive evidence for interpreting metatranscript-only TTN variants in genetically unresolved cases, although its diagnostic utility requires validation in larger more diverse titinopathy cohorts.