Background: Dilated cardiomyopathy (DCM) represents a genetically and phenotypically heterogeneous myocardial disease leading to systolic dysfunction and heart failure. While multiple causative genetic variants have been identified, the contribution of rare mutations in the actin alpha skeletal muscle (ACTA1) gene to cardiac pathology remains poorly characterized.
Case summary: We report a heterozygous missense variant in the ACTA1 (c.920T>G; p.(Met307Arg)) gene associated with progressive DCM in a patient with nemaline myopathy. This mutation was not previously described in humans, and leads to a methionine-to-arginine substitution at position 307. Despite the absence of overt heart failure symptoms and unremarkable cardiac biomarkers, echocardiography and cardiac magnetic resonance imaging demonstrated progressive left ventricular dilation and a continuous decline in left ventricular systolic function over nine years despite guideline-directed medical therapy.
Discussion: This case demonstrates the steep phenotypic deterioration in a patient with a newly described DCM-causing genetic variant in systemic myopathy. It illustrates the potential for progressive cardiac involvement in systemic skeletal muscle disorders and emphasizes the importance of genetic evaluation in patients with unexplained DCM. Comprehensive genotypic characterization may facilitate individualized risk assessment and enable earlier identification of disease progression to compensate for the existing mismatch between phenotypic variance and the currently establishes one-size-fits-all treatment approach. Understanding the link between genetic variants and transcriptomic or proteomic changes will be key for future DCM research.
