Development of a Cardiac Sarcomere Functional Genomics Platform to Enable Scalable Interrogation of Human <i>TNNT2</i> Variants

Abstract

Our study found that hypertrophic cardiomyopathy-associated <i>TNNT2</i> variants increased cardiac microtissue contraction, whereas dilated cardiomyopathy-associated variants decreased contraction, both of which paralleled changes in myofilament calcium affinity. Transcriptomic changes, including <i>NPPB</i> levels, directly correlated with sarcomere function and can be used to predict <i>TNNT2</i> variant pathogenicity.