Abstract: 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.

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