Beyond sarcomere genetics: proteomic insights into hypertrophic cardiomyopathy

Abstract Hypertrophic cardiomyopathy (HCM) has long been viewed as the archetypal monogenic disorder caused by pathogenic variants in the genes encoding components of the sarcomere. However, the fact that only one-third of HCM cases are genotype-positive, as well as other factors such as incomplete disease penetrance and marked phenotypic heterogeneity, challenge this reductionist view. Recent advances in mass spectrometry-based proteomics have provided new opportunities to interrogate human HCM myocardium at unprecedented depth and are reshaping our understanding of HCM pathobiology. In this mini-review, we summarize insights from both top-down and bottom-up proteomics studies showing that HCM is characterized by broad molecular remodeling across multiple cellular compartments, including the sarcomere, sarcoplasmic reticulum, cytoskeleton, mitochondria, and nucleus. Together, these studies support a model in which diverse HCM genotypes converge on shared downstream proteomic phenotypes and highlight proteomics as a powerful approach for defining disease mechanisms, modifiers, and therapeutic targets.