Genetic anticipation and cardiac conduction abnormalities in myotonic dystrophy type 1: implications for early stratification from a multicenter registry

Abstract

BACKGROUND: DM1 is an autosomal dominant disorder caused by unstable CTG repeats that expand over lifetime and in successive generations, contributing to genetic anticipation. Cardiac conduction abnormalities (CCAs) are a major source of morbidity and premature death in DM1, yet the influence of age at diagnosis, generation, and CTG repeat length on the timing and progression of cardiac involvement remains poorly defined. METHOD: This multicentric retrospective study included 549 adult DM1 patients from 16 hospitals in Spain. The primary composite endpoint comprised significant CCAs, device implantation, malignant ventricular arrhythmias and cardiac syncope. Patients were stratified by age-at-diagnosis (<40, 40-59, and ?60 years); birth generation (1920-1965, 1966-1990, 1991-2015), and CTG repeat length (<100, 100-599, and ?600). RESULTS: During follow-up, 33.1 % of patients experienced the primary endpoint. This risk was 4.7-fold higher in the youngest group versus the oldest group (HR 4.70; p < 0.001); 35-fold higher in the 3rd generation versus the 1st and increased progressively with longer CTG expansions. Device implantation rates were likewise higher in younger patients, later generations, and those with larger repeat lengths. CONCLUSION: The results demonstrate a striking anticipation pattern in the cardiac phenotype of DM1, with progressively earlier and more severe electrical disease paralleling CTG expansion across generations. Incorporating age at diagnosis, generational cohort, and genetic repeat burden into clinical assessment may enhance risk stratification and enable earlier, targeted rhythm surveillance and device therapy to prevent sudden cardiac death in DM1.