Cardiomyopathy Without Clinically Manifest Skeletal Myopathy in Patients with Variants in Skeletal Myopathy Genes: A Single-Center Cohort Study

Background/Objectives: Variants in genes classically associated with skeletal myopathies may be identified in patients with cardiomyopathy without clinically manifest skeletal muscle disease. We aimed to characterize the clinical, imaging, familial, and genetic features of this population. Methods: We conducted a single-center retrospective study of 33 patients with cardiomyopathy and no clinically manifest skeletal myopathy, comprising 31 laboratory-selected patients and two affected relatives from a previously published ACTA1 family. Clinical, familial, imaging, and genetic data were analyzed, incorporating available disease-specific variant classifications. Results: Median age at the beginning of cardiac follow-up was 47 years (range 16–77), and 42.4% were male. Dilated cardiomyopathy was the most frequent phenotype (22/33, 66.7%), followed by hypertrophic cardiomyopathy (8/33, 24.2%) and non-dilated left ventricular cardiomyopathy (3/33, 9.1%). ANO5 was the most frequently represented ascertainment gene (12/33, 36.4%). Among patients with complete data, 74.1% had no major conventional cardiovascular risk factors or significant coronary artery disease. Family history of cardiomyopathy was present in 43.8%, and 21 patients had additional genetic findings. Cardiac magnetic resonance was performed in 23 patients; late gadolinium enhancement was present in nine (39.1%), exclusively with non-ischemic patterns. Conclusions: The cohort describes heterogeneous cardiac presentations in patients carrying variants in skeletal-myopathy-associated genes without clinically manifest skeletal myopathy. These observations support further investigation of potential skeletal–cardiac phenotypic overlap and remain hypothesis-generating without establishing variant-level cardiac causality.