Dottorato in MEDICINA MOLECOLARE

Titolo della tesi: Cardiac Natural History and Genotype–Phenotype Correlations in Dystrophinopathies

Background: Duchenne and Becker muscular dystrophies (DMD/BMD) are dystrophinopathies with a well-established, life-limiting cardiac phenotype. This involvement is predominantly characterized by dilated cardiomyopathy, which progresses to heart failure the primary cause of mortality in this patient population. Existing natural history data are constrained by historically small cohort sizes (often n<200) and precede the modern era of prophylactic pharmacotherapy, limiting their current applicability. Furthermore, while genotype-phenotype correlations have been explored, prior analyses are frequently biased by cross-sectional designs and simplistic classifications of dystrophin mutations based on location rather than integrated molecular functional mechanisms. Objectives: This study is designed to: 1) Utilize a large, contemporary patient cohort to provide a robust, quantitative assessment of the cumulative risk of heart failure in DMD/BMD. 2) Determine the real-world prevalence of under-investigated cardiac complications, including arrhythmias, conduction disorders, and myocarditis. 3) Perform a comprehensive genotype-phenotype correlation analysis for heart failure manifestations, incorporating and validating relevant molecular pathophysiological hypotheses established in skeletal muscle research. Proposed Methods: We propose a longitudinal, multicenter study. A large cohort of genetically confirmed DMD/BMD patients will be assembled. Data collection will encompass comprehensive genetic sequencing, detailed cardiac phenotyping via advanced imaging, and long-term clinical follow-up. Genetic analysis will move beyond mutationn location to model the predicted functional impact on dystrophin protein domains and their presence/absence. Anticipated Significance: This study aims to generate an updated and reliable natural history of cardiac disease in DMD/BMD. By integrating deep genotyping with detailed longitudinal phenotyping, we seek to elucidate the molecular determinants of cardiac outcomes. The findings are expected to inform improved risk stratification; guide targeted therapeutic interventions and ultimately improve the management of cardiomyopathy in dystrophinopathies.