The genetics of aortopathies: Hereditary thoracic aortic aneurysms and dissections

Abstract

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.

Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies

“…The identification of genetic variants that cause hereditary forms of aneurysm provides the opportunity to clearly define the molecular deficiencies that initiate this disease. Several recent reviews have summarized the current list of approximately 30 genes involved in the development of either syndromic or non-syndromic forms of TAA [14,[184][185][186] (Figure 1B). Although criteria for inclusion vary, 11 genes are currently confirmed as "definitive" determinants of highly penetrant TAA based on the Clinical Genome Resource framework [187].…”

“…Mutations that cause TAA interfere with the function of genes that encode components of the ECM or proteins implicated in the transduction of either mechanical or biochemical signals in VSMCs [14,[184][185][186]. The list of known TAA-associated genes, mode of inheritance, the primary biochemical function perturbed by causal variants, and associated disease are described in Table 1.…”

“…In contrast, TAAs in hereditary non-syndromic thoracic aortic disease are not usually associated with overt defects in other connective tissues [13]. Several causative genes for both syndromic and non-syndromic TAA have been identified, leading to a better understanding of the mechanisms by which this condition develops [14]. In this review, we summarize critical features of the healthy aortic wall, the molecular functions compromised by TAA-associated mutations, and the proposed mechanisms by which they disrupt aortic homeostasis.…”

Aortic arch geometry predicts outcome in patients with Loeys–Dietz syndrome independent of the causative gene

“…LDS is an aggressive HTAD associated with a high risk of developing aortic and arterial aneurysms, dissections, and ruptures at a young age and at smaller aortic diameters than in other disorders. The clinical spectrum of LDS includes patients with minimal or no dysmorphic features, and patients with typical craniofacial, skeletal, and cutaneous features, which usually present with a more severe aortic phenotype (Chou & Lindsay, 2020; MacCarrick et al, 2014). The Montalcino Aortic Consortium has shown that type B aortic dissections tend to be more frequent as the presenting feature in patients with a TGFβR2 mutation compared with those with a TGFβR1 mutation and aortic root diameter at the time of type A aortic dissection tended to be smaller in patients carrying a TGFβR2 mutation (Jondeau et al, 2016).…”

Tracking an Elusive Killer: State of the Art of Molecular-Genetic Knowledge and Laboratory Role in Diagnosis and Risk Stratification of Thoracic Aortic Aneurysm and Dissection

“…Non-syndromic TAAs account for 95% of all TAA cases [ 6 ] and are further classified as sporadic or familial, in the case of at least one of the first-degree family members being affected [ 9 ]. The different presentations of TAA share similarities with regards to the molecular pathophysiology underlying dilatation development (impaired extracellular matrix (ECM)), collagen homeostasis, alteration of the TGF-β signaling pathways, disruption of smooth muscle and cytoskeletal apparatus, and, even if with different penetrance, a significant heritability [ 10 ].…”