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

Palma-Jiménez, M.; Ramirez-Carvajal, L.; Corrales, E.; Olafson, H.; Wang, E. T; Morales-Montero, F.

Abstract:

Background Myotonic dystrophy type 1 (DM1) is a multisystem disorder with autosomal dominant inheritance, caused by the abnormal expansion of the CTG triplet in the DMPK gene. Biomarker discovery in DM1 is crucial for monitoring disease progression. Methods We performed RNA sequencing on blood, skin and muscle samples from the same patients to assess splicing events. Mis-splicing events were identified using the Mann-Whitney U rank-sum test, and per cent spliced in for exons was correlated with repeat expansion size using Spearman’s correlation. We also examined the relationship between mis-splicing and disease severity through Fisher’s exact test and correlation analyses. Results We identified 937, 384 and 1216 mis-splicing events in muscle, blood and skin, respectively. Of these, 52 exons in muscle and 10 in blood correlated with estimated progenitor allele length (false discovery rate (FDR) <0.1), but none in skin. Notably, nine exons in blood correlated with total muscle mis-splicing (FDR<0.05), suggesting their potential as biomarkers of severity. Conclusion This is the first study to identify splicing dysregulation in blood and skin in patients with DM1 and identify novel potential blood-based mis-splicing biomarkers for disease severity. The correlation between several blood exons and the muscle splicing dysregulation indicates that blood-based biomarkers can be valuable for assessing disease severity, monitoring disease progression and evaluating treatment efficacy. Larger sample sizes may be necessary to clarify the relationship between mis-splicing and disease severity.

Año:

2025

Tipo de publicación:

Artículo

Journal:

Journal of Medical Genetics

Mes:

16 Octubre

DOI:

https://doi.org/10.1136/jmg-2025-110919