TANGO2-deficient disorder (TDD) is an autosomal recessive genetic disease caused by biallelic loss-of-function variants in TANGO2 gene. TDD-associated cardiac arrythmias are typically recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Here, we established novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD including prolonged field potential duration, premature ventricular contractions, and decreased spike amplitude. These conduction abnormalities normalize in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant by CRISPR editing. We further demonstrate that folate greatly abolishes the ventricular ectopy and conduction abnormalities. Data from this study taken together with clinical data from TDD patients supports the use of B-vitamins to mitigate cardiac crisis in TDD patients.

Bi-allelic loss-of-function mutations in TANGO2 (Transport and Golgi Organization protein 2) cause a rare multiorgan genetic disorder. Despite normal cardiac function at baseline, patients may experience lethal cardiac arrhythmias during crises often associated with metabolic stresses such as fasting, viral illness and fever. The molecular function of TANGO2 remains largely unknown. Previous studies have suggested a functional association with the mitochondrion, however definitive evidence is lacking. Further, functional impact of TANGO2 deficiency on mitochondrial function has not been investigated in a cardiac model. In this study, we utilized a recently developed patient-derived induced pluripotent stem cell differentiated cardiomyocytes (iPSC-CM) model by our group, along with patient-derived dermal fibroblast model, to interrogate whether loss of TANGO2 function leads to defective mitochondrial function. Both baseline and fasting condition were investigated. Oxygen consumption rate (OCR) was measured in Seahorse assays to assess mitochondrial function in vitro. The results showed both TANGO2 deficient dermal fibroblasts and iPSC-CM had no apparent defects in mitochondrial oxidative phosphorylation (OXPHOS) function under either baseline or fasting condition. Based on our study, we conclude that the lethal cardiac arrhythmias in TANGO2 patients are unlikely to be related to impaired mitochondrial OXPHOS function in the cardiomyocytes.