The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections

Aortopathies encompass a variety of inherited and acquired pathologies that increase risk of life-threatening dissection or rupture. Identifying individuals with hereditary thoracic aortic aneurysm and dissection (HTAAD) for longitudinal monitoring, medical therapy, or elective and preventative repair is paramount to reduce risk of cardiovascular-related mortality and complications from dissection and rupture. Over the past couple of decades, pathogenic variants in numerous genes have been identified in relation to HTAAD. The genetic diagnosis can help stratify patient risk and provide guidance on medical treatment, timing of prophylactic surgical repair, as well as longitudinal surveillance and imaging. Implicated genes and their associated proteins have been found to act on a diverse variety of pathways, cells and structural components linked to transforming growth factor beta (TGF-β) signaling pathways, disruption of the vascular smooth muscle cell contractile apparatus, and primary disruption of extracellular matrix homeostasis. This review describes relevant genetic variants that may help identify and guide the management of hereditary thoracic aortic aneurysms and dissections.