The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective

Abstract

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on genes that have been linked to dissection at diameters <5.0 cm, the current lower bound for surgical intervention. Genetic screening tests to identify patients with TAAD associated mutations that place them at high risk for dissection are also discussed.

Keywords: genetic screening; genetics; non-syndromic TAAD; syndromic TAAD; thoracic aortic aneurysm and dissection (TAAD).

Figure 1

Ascending aortic dimensions for prophylactic surgical intervention. Abbreviations: ECM, extracellular matrix; SMC, smooth muscle cell; TAAD, thoracic aortic aneurysm and/or dissection; TGF, transforming growth factor. © 2020 by Thieme Medical Publishers Inc. [9]

Figure 2

Overall frequency distribution of TAAD associated variants. FBN1 was the most frequently mutated gene in this patient cohort. © 2020 by Edi.Ermes. [30]

Figure 3

Positive family history of aortic dissection (FHAD) significantly increases the risk of developing a new dissection in unaffected family members, with (A) higher number of dissection events; (B) a younger age at dissection; (C) shorter duration of exposure prior to dissection; and (D) higher annual probability of aortic dissection. © 2020 by Elsevier. [77]

Figure 4

The number of mutations identified to be causative of TAAD has steadily increased since 2012. © 2020 by Thieme Medical Publishers Inc. [9]

Figure 5

The data demonstrate that RNA signatures show promise as a biomarker for TAAD. A) Scaled down representation of the entire cluster of the 1199 signature genes and 61 whole blood samples. B) Experimental dendrogram displaying the clustering of the samples into two main branches: the TAA branch (red) and the control branch (blue) with only a few exceptions. © 2020 by Wang et al. [134]

Figure 6

Proposed flow chart for a dedicated screening program for relatives of patients affected by non-syndromic diseases of the thoracic aorta. Note the importance of genetic screening in stratifying patients. BAV indicates bicuspid aortic valve; CT, computed tomography; FDRs, first-degree relatives; MRI, magnetic resonance imaging; NS-TAD, non-syndromic thoracic aortic disease; SDRs, second-degree relatives; TTE, transthoracic echocardiogram. © 2020 by Mariscalo et al. [138]