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 (?) 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, ? 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. Overall design: The samples used in this study were derived from 35 DM1 patients, with RNA purified from three different tissues: blood, skeletal muscle (tibialis anterior-TA), and skin. The patient cohort was categorized into four clinical subtypes: two late-onset, twenty-four classical, four pediatric, and two congenital cases, along with three apparently asymptomatic individuals.