Young and early-onset dilated cardiomyopathy with malignant ventricular arrhythmia and sudden cardiac death induced by the heterozygous LDB3, MYH6, and SYNE1 missense mutations.

Background The whole exome sequencing (WES) with targeted gene analysis is an effective diagnostic tool for cardiomyopathy. The early-onset sudden cardiac death (SCD) was commonly associated with dilated cardiomyopathy (DCM) induced by pathogenic genetic mutations. Methods In a Chinese Han family, the patient of 24 years old occurred with early-onset and DCM and died of SCD associated with ICD storms induced by repetitive ventricular tachycardia/fibrillation (VT/F). Genomic DNA samples of peripheral blood were conducted for WES and Sanger sequence. Then, we performed bioinformatics analysis for 200 genes susceptible to cardiomyopathies and arrhythmias. Further, we analyzed how the potential pathogenic mutations affecting the secondary structure, hydrophobicity, and phosphorylation of amino acids, protein properties, and their joint pathogenicity by ProtParam, SOPMA, and ORVAL algorisms. The protein-protein interaction was analyzed by STRING algorism. Results The mutations of LDB3 p.M456R, MYH6 p.S180Y, and SYNE1 p.S4607F were identified as "Damaging/Deleterious." The SYNE1 (p.S4607F) increased one of alpha helix and decreased one of beta sheet. The LDB3 (p.M456R) reduced one of beta sheet and increased one of beta turn. The MYH6 (p.S180Y) decreased two of beta sheets and four of beta turns, but significantly increased twelve coils. The hydrophobicity of amino acid residues and their adjacent sequences were decreased by LDB3 (p.M456R) and MYH6 (p.S180Y), and significantly increased by SYNE1 (p.S4607F). The mutations of LDB3 (p.M456R), SYNE1 (p.S4607F), and MYH6 (p.S180Y) resulted in the phosphorylation changes of the corresponding amino acid sites or the nearby amino acid sites. The pairwise combinations of LDB3, MYH6, and SYNE1 mutations have the high probability of causing disease, especially the highest probability for SYNE1 and LDB3 mutations. There was obviously indirect interaction of the proteins encoded by SYNE1, LDB3, and MYH6. Conclusions The multiple heterozygous mutations of SYNE1, LDB3, and MYH6 may be associated with young and early-onset of DCM and SCD.