Molecular Genetics of Aortic Aneurysms and Aortic Dissections

Abstract

A genetic predisposition to aortic aneurysms and dissections can occur as part of a genetic syndrome, such as Marfan and Loeys‐Dietz syndrome, or as an isolated manifestation without other systemic features, referred to as familial thoracic aortic aneurysms and dissections. These genetic disorders are inherited as autosomal dominant conditions with reduced penetrance and variable expressivity in terms of aortic disease presentation, age of onset and extent of cardiovascular and other systemic involvement. Mutations in the FBN1, TGFBR1, TGFBR2, SMAD3, SMAD4, TGFB2, ACTA2, MYH11, MYLK and PRKG1 have been identified in patients with syndromic and non‐syndromic TAAD, emphasising the important roles of the transcription growth factor beta signalling pathway and smooth muscle contraction in aortic disease development.

Key Concepts

  • Thoracic aortic aneurysms and dissections or TAAD can occur as part of a genetic syndrome, such as Marfan syndrome, Loeys‐Dietz syndrome or as an isolated manifestation without syndromic features.
  • Approximately 20% of patients with TAAD who do not have Marfan syndrome or related disorder have a similarly affected relative, referred to as familial thoracic aortic aneurysm and dissection or FTAAD.
  • Marfan syndrome, Loeys‐Dietz syndrome and FTAAD are primarily inherited in an autosomal dominant pattern with reduced penetrance and variable expressivity.
  • FTAAD is a genetically and clinically heterogeneous group of disorders caused by mutations in several genes, including FBN1, TGFBR1, TGFBR2, SMAD3, SMAD4, TGFB2, ACTA2, MYH11, MYLK and PRKG1.

Keywords: aortic aneurysm; aortic dissection; genetics; transcription growth factor beta signalling; smooth muscle; actin; myosin

Figure 1. Anatomical location and classification of aortic aneurysms and dissections. (a) Location of aortic aneurysms. (b) Classification of thoracic aortic dissections. Modified with permission from D. M. Milewicz, et al. . © Annual Reviews.
Figure 2. Radiographic imaging showing (a) an aortic root aneurysm at the level of the sinuses of Valsalva and sparing the ascending aorta and (b) ascending aortic aneurysm sparing the sinuses of Valsalva. Modified with permission from D. M. Milewicz, et al. . © Annual Reviews.
Figure 3. Aortic pathology associated with thoracic aortic aneurysm and dissection. All panels are oriented with the adventitia at the top and the intima at the bottom. Haematoxylin and eosin (H&E) staining of aortic sections from (a) a control and (b) patient with TAAD, illustrating medial degeneration with fragmentation of elastic fibres and loss of smooth muscle cells. Movat staining of aortic sections from (c) a control and (d) patient with TAAD showing fragmentation of elastic fibres (stained black), loss of smooth muscle cells (cells stained red and nuclei stained violet) and accumulation of proteoglycans (stained blue) in the medial layer. 40× magnification; scale bar represents 500 μM for all panels. Modified with permission from D. M. Milewicz, et al. . © Annual Reviews.
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Regalado, Ellen S, and Milewicz, Dianna M(Mar 2015) Molecular Genetics of Aortic Aneurysms and Aortic Dissections. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024366]