Cardiomyopathy phenotypes caused by a heterozygous MYBPC3 mutation revealed in different hiPSC cardiac models

Hypertrophic cardiomyopathy (HCM) is a complex cardiac disorder caused by mutations in sarcomeric protein genes, showing variable penetrance and disease severity among patients. Key pathological features include left ventricular hypertrophy, myofibrillar disarray and contractile defects. Here, we used human induced pluripotent stem cells (hiPSCs) carrying the MYBPC3-c.2373insG mutation to investigate disease phenotypes across three in vitro platforms: cardiac microtissues (cMTs) generated from pre-differentiated cells, cardioids formed directly from hiPSCs and 2D hiPSC-derived cardiomyocytes. Both 3D models exhibited either altered contractile properties or calcium transients compared to isogenic controls, mirroring hypocontractility which is observed in some patients. In contrast, MYBPC3-c.2373insG hiPSC-derived cardiomyocytes cultured in 2D showed disrupted sarcomere organization and altered metabolism with increased oxygen consumption rate, but no measurable contractility defects. In addition, cMTs displayed a haploinsufficient phenotype, consistent with clinical observations in patients harbouring this mutation. Together, these findings show that different features of HCM pathology may best be revealed using different in vitro models, underscoring the need to select systems appropriate to the biological question. This work provides a platform to further explore the mechanisms underlying HCM, offering insights into how this condition might be more effectively studied and, eventually, treated.