DMD Gene Variants and Cardiac Dysfunction in Young Males With Dystrophinopathies

Correlation of Pathogenic Variants in the DMD Gene With Cardiac Dysfunction in Male Children, Adolescents, and Young Adults With Dystrophinopathies: A Pilot Study

The goal of this observational study is to investigate whether the type, location, and extent of pathogenic variants in the DMD gene are associated with cardiac dysfunction in male children, adolescents, and young adults with dystrophinopathies. The study also evaluates whether cardiac biomarkers and electrocardiographic findings can facilitate the early identification of cardiac involvement. Participants will undergo electrocardiography, blood sampling for cardiac biomarker assessment, and transthoracic echocardiography, with cardiac dysfunction evaluated using ejection fraction (EF) and global longitudinal strain (GLS).

Pathogenic variants in the DMD gene lead to a spectrum of clinical phenotypes known as dystrophinopathies, with Duchenne muscular dystrophy and Becker muscular dystrophy representing the most common forms. Beyond progressive skeletal muscle weakness, a substantial proportion of patients have cardiac involvement, often progressing to dilated cardiomyopathy -a major cause of morbidity and the leading cause of mortality in this population. Although cardiac involvement is well recognized in dystrophinopathies, the relationship between specific DMD gene variants and the severity or pattern of cardiac dysfunction has not been fully clarified.

This observational pilot study is designed to investigate the association between the type, location, and extent of pathogenic variants in the DMD gene and cardiac dysfunction in male children, adolescents, and young adults aged 2 to 24 years with genetically confirmed dystrophinopathies. In addition to evaluating genotype-cardiac phenotype associations, the study explores whether cardiac biomarkers, electrocardiographic abnormalities, age, ongoing pharmacological treatment, and lipid-related parameters, including non-HDL cholesterol, are associated with early cardiac involvement.

Participants will undergo a structured clinical and cardiac evaluation, including collection of demographic and clinical data, medical history, pharmacological treatment, and comorbidities. Blood samples will be collected at the baseline assessment for measurement of cardiac biomarkers and lipid-related parameters. Cardiological evaluation will be performed in all participants and will comprise electrocardiography and transthoracic echocardiography. Echocardiographic assessment will include both conventional and deformation-based indices of left ventricular systolic function, including ejection fraction and global longitudinal strain.

By integrating genetic, biochemical, electrocardiographic, and echocardiographic data, this multidimensional approach seeks to improve understanding of genotype-cardiac phenotype associations, facilitate earlier recognition of cardiac involvement, and contribute to more individualized monitoring and clinical management in patients with dystrophinopathies.

Inclusion Criteria:

• Male sex
• Age between 2 and 24 years at the time of enrollment
• Genetically confirmed dystrophinopathy with a pathogenic or likely pathogenic variant in the DMD gene
• Genetic confirmation based on at least one validated method, including MLPA, NGS, Sanger sequencing, array-CGH, or qPCR
• Written informed consent from parents or legal guardians and, where applicable, consent from the participant

Exclusion Criteria:

• Absence of a genetically confirmed diagnosis of dystrophinopathy, including:
• diagnosis based solely on muscle biopsy without molecular confirmation of a pathogenic or likely pathogenic DMD gene variant
• absence of a confirmed pathogenic variant in the DMD gene, even if maternal carrier status has been identified, unless repeat genetic testing confirms a pathogenic variant in the participant
• Presence of congenital heart disease or other genetic disorders causing primary cardiomyopathy
• Presence of other neuromuscular disorders
• Female carriers, including both manifesting and asymptomatic carriers
• Comorbidities that may independently affect cardiac function, such as severe arterial hypertension, diabetes mellitus, or chronic kidney disease