In this report, we describe three ACM cases with the homozygous <i>DSG2</i> c.1592T>G (p.F531C) variant genotype combined with additional heterozygous cardiomyopathy-related genetic mutations that cause aggravated clinical manifestations and worse clinical outcomes.<h4>Case presentation</h4>The three reported probands demonstrated similar clinical presentations such as heart failure, cardiac enlargement, and lethal arrhythmias. The gene discussed is DSG2; the disease is cardiomyopathy.