We firstly reported that the multiple heterozygous mutations of SYNE1 p.S4607F, LDB3 p.M456R, and MYH6 p.S180Y with high joint pathogenicity may induce abnormal indirect protein–protein interactions through changing their hydrophobicity and phosphorylation of amino acids, which therefore led to young early‐onset and severe DCM, and subsequent SCD associated with VT/F. Here, SYNE1 is linked to familial dilated cardiomyopathy.