Seeger T, et al. - Researchers utilized human isogenic induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) to determine the molecular mechanisms underlying the pathogenesis of hypertrophic cardiomyopathy (HCM) related to myosin-binding protein C3 (MYBPC3) premature termination codon (PTC) mutations. They included HCM patients harboring MYBPC3 PTC mutations (p.R943x; p.R1073P_Fsx4) and generated isogenic iPSC lines from them using genome editing. In the iPSC-CMs, they carried out comprehensive phenotypic and transcriptome analyses. In mutant iPSC-CMs, significantly reduced mRNA expression levels of MYBPC3 were observed, with similar protein levels seen among isogenic iPSC-CMs. This finding indicated there was no contribution of haploinsufficiency of MYBPC3 to the pathogenesis of HCM in vitro. Overall, in the absence of significant haploinsufficiency of MYBPC3 protein, aberrant calcium signaling and molecular dysregulations were shown by iPSC-CMs carrying MYBPC3 PTC mutations. This investigation offers the first evidence of the direct link between the chronically activated nonsense-mediated decay pathway and HCM disease development.