Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a pseudo QRS complex suggesting reduced inward current(s). Voltage clamp analysis of I-Ca showed no difference in the magnitude of current. Measurements of I-Na reveal a 60% reduction in I-Na density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of I-Na was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of I-Na due to a mutation in PKP2 coupled with and a gain of function in I-K,I-ATP due to a mutation in ABCC9.

Automated summary

Human induced pluripotent stem cell-derived cardiomyocytes are used for genetic models of cardiac diseases. An arrhythmia syndrome consisting of Early Repolarization Syndrome and Short QT Syndrome was reported in a patient with six mutations, with functional alterations examined in patient-derived cells. The study revealed abnormal electrophysiological activity in the patient's cardiomyocytes, suggesting potential genetic causes for the syndrome.