Heart cells differentiated from human induced pluripotent stem cells (hiPSCs) offer much promise for creating models of genetic cardiac diseases “in a dish”. Indeed, we and others have demonstrated that cardiomyocytes generated from hiPSCs either derived from patients or in which specific mutations have been genetically introduced, capture key aspects of the disease pathology. An example is inherited cardiac rhythm disorders such as Long QT Syndrome, where the gene KCNH2 is mutated in one-third of patients.
However, a key feature of this channelopathy is variable disease manifestation in part due to the location and type of mutation, complicating efforts to predict patient risk. Recently we have demonstrated that phenotypic differences related to KCNH2 mutations could be captured by hiPSC-derived cardiomyocytes (hiPSC-CMs) under genetically matched conditions. While these results support hiPSC-CMs as strong candidates for evaluating the underlying severity of individual mutations in humans, a larger panel of variants on the same genetic background require further evaluation. As this is not feasible with standard gene editing techniques, we have developed a cost-effective and efficient procedure to simultaneously generate panels of hiPSCs carrying different KCNH2 variants in the same cell line and genomic context. Such panels might not only improve patient risk stratification for example by evaluating the pathogenicity of rare variants but will also find applications in the development of patient-specific pharmacotherapies, further demonstrating the utility of hiPSCs in disease modelling.
