Spatial genomics of the cardiac sarcomere

Structure-function mapping of proteins has improved our understanding of disease mechanisms and protein domains while human population genetics has provided a window into variational tolerance that can be modeled at a structural level. Here, to reveal novel insight into the cardiac sarcomere, the motor unit of the heart, we develop a novel analytical framework to integrate data from over 17,000 patients with hypertrophic cardiomyopathy (HCM) and combine it with two population-scale genomic databases that incorporate data from more than 1.2 million individuals. We integrate in silico genetic predictions of gene variant pathogenicity with 3 dimensional integrative spatial scanning across multiple structural models of cardiac motor proteins. Results reveal both recognized and novel regions of structural variant intolerance across the critical genes of the cardiac sarcomere including novel insights into protein function. We discuss the structural relevance of mutational enrichment in the context of sarcomere organization and destabilization of sequestered myosin leading to hypercontractility seen in HCM, by incorporating the recently defined high-resolution structure of human cardiac myosin filament. We extend and validate these findings through pathogenic variant class enrichment and reveal novel associations with the earlier onset of disease in a large clinical cohort. In summary, our study provides a multi-dimensional framework for integrating structural, genomic, and modeling data to reveal novel insight into the cardiac sarcomere.