Analysis of Muscle and Blood RNA Samples from Patients with Myotonic Dystrophy Type 1 Reveals the Presence of New Mis-Splicing Biomarkers of Disease Severity

To investigate biomarkers of disease severity in patients with myotonic dystrophy type 1 (DM1), we conducted RNA sequencing in blood, skin, and skeletal muscle (tibialis anterior, TA) from the same DM1 patients. This analysis revealed 937, 384, and 1216 mis-splicing events in muscle, blood, and skin, respectively. We determined the percent splice-in (ψ) values for 52 exons in muscle and 10 exons in blood, which correlated with repeat expansion sizes using the ePAL method; no such correlations were observed in skin. Notably, ψ values for nine exons in blood correlated with total splicing dysregulation in muscle (FDR < 0.05), suggesting their potential as biomarkers for DM1 disease severity. This study marks the first identification of: 1) splicing dysregulation in blood and skin, confirming tissue-specific splicing dysregulation, and 2) blood-based DM1 mis-splicing biomarkers of disease severity. For the first time, we present blood mis-splicing biomarkers that serve as a proxy for muscle splicing dysregulation, meeting the criteria for an ideal severity biomarker by being minimally invasive and capable of monitoring disease progression.