Titin truncating variant associated with atrial fibrillation leads to cell type-specific effects in atrial and ventricular patient hiPSC-CM models

Protein truncating mutations in the titin gene are associated with increased risk of atrial fibrillation (AF). However, little is known regarding the underlying pathophysiology. We identified a heterozygous titin truncating variant in a patient with unexplained early-onset AF using whole exome sequencing. We used atrial and ventricular patient induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), CRISPR/Cas9 genetic correction, and engineered heart tissue (EHT) constructs to evaluate the impact of the titin truncating variant on electrophysiology, sarcomere structure, contractility, and gene expression. Overall design: Atrial-like and ventricular-like patient iPSC-CMs were cultured in a 2D/monolayer format or used to generate EHT constructs. 3 biological replicates per sample type (culture format, cell type, titin genotype) were sequenced to compare the effects of the titin truncating variant on gene expression in atrial and ventricular iPSC-CMs and EHTs.