5 - Heritable Thoracic Aortic Disease: Single Gene Disorders Predisposing to Thoracic Aortic Aneurysms and Acute Aortic Dissections

Abstract

Thoracic aortic disease, consisting of thoracic aortic aneurysm, acute aortic dissection, and aortic rupture, can be triggered by genetic variants. Marfan syndrome established that mutations in a single gene (FBN1) can predispose to highly penetrant thoracic aortic disease. Subsequently, additional genes were identified that similarly confer a high risk for thoracic aortic disease; currently 11 genes are confirmed to predispose to thoracic aortic disease with autosomal dominant inheritance. These validated genes encode proteins involved in vascular SMC contraction, the extracellular matrix, and transforming growth factor (TGF)-β signaling pathways and include the following genes: FBN1 (encodes fibrillin-1), LOX (lysyl oxidase), MYH11 (smooth muscle myosin heavy chain 11), ACTA2 (smooth muscle α-actin 2), MYLK (myosin light chain kinase), PRKG1 (cGMP-dependent protein kinase type I), COL3A1 (α-1 procollagen, type III), TGFBR2 (TGF-β receptor type II), TGFBR1 (TGF-β receptor type I), TGFB2 (TGF-β2), and SMAD3 (mothers against decapentaplegic homolog 3). Clinical data support that the specific gene for thoracic aortic disease should dictate the clinical management of aortic and other vascular diseases in these patients, including the timing of surgical repair of an aneurysm and the risk for additional vascular diseases.