Somatic Mutations in Cardiovascular Disease

Abstract

Advances in population-scale genomic sequencing have greatly expanded the understanding of the inherited basis of cardiovascular disease (CVD). Reanalysis of these genomic datasets identified an unexpected risk factor for CVD, somatically acquired DNA mutations. In this review, we provide an overview of somatic mutations and their contributions to CVD. We focus on the most common and well-described manifestation, clonal hematopoiesis of indeterminate potential. We also review the currently available data regarding how somatic mutations lead to tissue mosaicism in various forms of CVD, including atrial fibrillation and aortic aneurism associated with Marfan Syndrome. Finally, we highlight future research directions given current knowledge gaps and consider how technological advances will enhance the discovery of somatic mutations in CVD and management of patients with somatic mutations.

Keywords: cardiovascular diseases; clonal hematopoiesis; coronary artery disease; genomics; mutation.

Figure 1.. Mechanisms of somatic mutations giving rise to tissue mosaicism

Mosaicism results from somatic DNA mutations obtained throughout the lifespan of the individual. Mutations arise from a variety of mechanisms including base mismatches, single and double strand breaks, and various crosslinks (left panel). When these mutations occur in driver genes within hematopoietic stem cells (blue cells), a survival advantage can be conferred, leading to the enhanced proliferation of the mutated cells (right panel). Clonal hematopoiesis of indeterminate potential results from this selective advantage. Created with BioRender.com. Illustration Credit: Ben Smith.

Figure 2.. Somatic mutations in cardiovascular disease

Somatic mutations can lead to a variety of manifestations in cardiovascular disease ranging from conduction system alterations to the development of atherosclerotic coronary disease. The most commonly identified somatic mutations are CHIP mutations within hematopoietic stem cells which lead to deleterious downstream effects across the cardiovascular system. Due to technological advancements, somatic mutations are increasingly being identified and characterized across cardiovascular tissues. Created with BioRender.com. Illustration Credit: Ben Smith.