Implication ofTITINVariations in Dilated Cardiomyopathy: Integrating Whole Exome Sequencing With Molecular Dynamics Simulation Study

Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure, characterized by ventricular dilation and impaired systolic function. Variations in the TITIN ( TTN) gene, which encodes the giant muscle protein TTN, play a pivotal role in the genetic underpinnings of DCM. We conducted WES on 15 patients (5 familial and 10 sporadic) diagnosed with idiopathic DCM and identified 88 exonic variants including four novel variants. These variants were predominantly located in the A-band region (39 variants) of TTN, a critical region for its mechanical stability and interaction with other sarcomeric proteins, followed by the I-band domain (33 variants), Z-disc domain (7 variants) and M-band region (9 variants). To discern the functional repercussions of these variations, we performed several bioinformatics analyses including pathogenicity prediction, protein stability, and protein-protein docking followed by MD simulations on both wild-type and mutant TTN fragments with their corresponding interacting partners (TCAP, MYH7, LMNA). We revealed that variations in the A-band domain significantly alter the protein’s structural dynamics, leading to decreased mechanical stability and altered protein-protein interactions. These changes are likely to disrupt sarcomere function, thereby elucidating their role in the pathogenesis of DCM. Graphical abstract