Pathogenic variants in myoferlin (MYOF) cause arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by fibrofatty remodeling and sudden cardiac death. Approximately 40% of cases remain genetically unexplained. Researchers identified a pathogenic variant in the MYOF gene, which encodes a calcium-binding protein in heart muscle cells. In families with ACM, they found a heterozygous MYOF p.G1654S variant in four cases. In patient cells, this variant caused calcium handling defects and increased arrhythmias, which were rescued by genomic correction. MYOF interacts with the CaV1.2 protein, and drugs such as verapamil improved arrhythmias. Mice with heterozygous MYOF knockout showed systolic dysfunction and fibrosis. These findings establish MYOF as a causative ACM gene and potential therapeutic target.