Single nucleus RNA sequencing identifies PLXNA4 upregulation in end-stage arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic form of heart disease often caused by mutations in desmosomal proteins. We carried out single-nucleus RNA sequencing (snRNA-seq) on 11 non-failing and 8 ARVC patient right ventricular samples and transcriptionally profiled 139,347 nuclei. We identified over 4,400 differentially expressed protein-coding genes between non-failing and ARVC samples across cell types. When compared to dilated, hypertrophic, and ischemic cardiomyopathy, we found that end-stage ARVC is transcriptionally similar to other forms of end-stage heart failure. Despite broad transcriptional similarities, we identified seven cardiomyocyte genes and six fibroblast genes that were uniquely dysregulated in ARVC and validated PLXNA4 as a gene with uniquely increased expression in cardiomyocytes in ARVC compared to other cardiomyopathies. Overexpression of PLXNA4 in hiPSC-derived ventricular cardiomyocytes induced immune response gene expression, suppressed calcium signaling, and altered cardiomyocyte electrophysiology, suggesting PLXNA4 may contribute to these pathways in ARVC.