The Role of the OBSCN Gene in Cardiomyopathy: A Review of Molecular Mechanisms and Clinical Significance

Cardiomyopathies are genetically heterogeneous myocardial diseases that can lead to heart failure, arrhythmias, and sudden cardiac death. OBSCN encodes obscurin, a giant sarcomere-associated protein involved in sarcomere organization, cytoskeletal coupling, calcium handling, and cell-cell adhesion signaling. This review synthesizes current evidence on OBSCN variants in cardiomyopathy, focusing on their spectrum, phenotypic associations, and potential pathogenic mechanisms. Curated variants were systematically interpreted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines. Putative truncating variants predominated among variants of uncertain significance, and hypertrophic cardiomyopathy was the most frequently reported phenotype. Co-occurring variants in established or candidate cardiomyopathy-associated genes were reported for some OBSCN variants, particularly missense variants. However, co-occurrence alone does not establish an independent pathogenic contribution, oligogenic inheritance, or a genetic modifier effect. Potential mechanisms include obscurin insufficiency, destabilization of sarcomeric scaffolding, impaired sarcoplasmic reticulum coupling, dysregulated calcium homeostasis, altered mechanotransduction, and defective intercellular adhesion. Overall, OBSCN is an emerging but incompletely characterized cardiomyopathy-associated gene, and truncating variants warrant further clinical and mechanistic investigation.