Journal of medical genetics · 2026
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.
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Palma-Jiménez Melissa, Ramirez-Carvajal Lisbeth, Corrales Eyleen, Olafson Hailey, Wang Eric T, Morales Fernando
Аннотация
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.
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.