DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Diagnostics

Background:

• Dilated cardiomyopathy (DCM) linked to dystrophin (DMD) gene variants causes severe heart failure and arrhythmias.
• Early identification of at-risk individuals is essential for improved patient outcomes.

Purpose of the Study:

• To evaluate the diagnostic yield of genetic testing for X-linked primary DCM.
• To identify specific genetic variants and assays for diagnosing DMD-associated cardiomyopathy.

Main Methods:

• Genetic testing of 40 male probands with primary DCM using multi-gene panels, PCR, and array CGH.
• Assessed variant location relative to dystrophin isoforms and exon usage.
• Evaluated myocardial and blood telomere length as markers of cardiac dysfunction.

Main Results:

• Pathogenic DMD variants were found in 12.5% of probands, with 3/4 identified only by targeted structural variant assays.
• Autosomal gene variants (TTN, BAG3, LMNA, RBM20) were found in 37.5% of DMD-negative probands.
• Reduced myocardial telomere length was observed in DCM patients, but not in blood samples.

Conclusions:

• Multi-gene panels have limited utility for detecting DMD-associated cardiomyopathy; specific structural variant assays are necessary.
• Differentiating X-linked DCM from autosomal causes is critical for family counseling and management.