Mechanisms of Pathogenicity of Hypertrophic Cardiomyopathy-Associated Troponin T (TNNT2) Variant R278C +/- During Development.

Hypertrophic cardiomyopathy (HCM) is the leading known cause of sudden cardiac arrest in the young. Thin-variant associated HCM variants make up to 15% of familial HCM yet their molecular mechanisms remain less clear relative to thick filament variants. Here, we employ computational modeling, human cardiac recombinant/reconstituted thin filaments (hcRTF), and hiPSC-CMs to study the thin filament R278C variant, revealing its extensive pathogenicity and potential mechanisms by which it can lead to HCM and sudden death. Mavacamten, the recently FDA-approved treatment, was effective in alleviating contractile dysfunction in R278C hiPSC-CMs, positing it as a potential therapy for thin filament HCM.