Genome-wide association mapping for cardiomyocyte ploidy identifies Shroom3 as responsible for hyperpolyploidy and ventricular dilation [bulkRNA-Seq]

However, our understanding of the comprehensive mechanisms governing CM ploidy and its relationship with heart physiology has been hindered by a lack of experimental tools. To address this issue and uncover novel genetic regulators, we surveyed CM ploidy across a new genetic resource known as the Hybrid Rat Diversity Panel and founnd significant variation in ploidy phenotypes across the panel.

Using select rat strains with divergent displays of CM ploidy, we found that hyperpolyploidization (≥8N) positively correlates with various physiological parameters namely left ventricular dilation and reduced ejection fraction. Genome-wide association mapping identified several loci significantly associated with frequency of hyperpolyploid CMs. Investigation of genes harboring damaging protein coding variants within these loci identified enrichment of cytoarchitectural genes, of which the ACTIN-binding protein, Shroom3, was found to be strongly and specifically expressed in CMs and harbors 7 damaging protein coding variants.