Abstract
Thoracic aortic aneurysms are prevalent in the Western population and are often caused by genetic defects. If undetected, aneurysms can dissect or rupture, which are events associated with a high mortality rate. Hitherto no cure exists other than elective surgery if aneurysm dimensions reach a certain threshold. In the past decades, genotype-phenotype associations have emerged that enable clinicians to start stratifying patients according to risk for dissection. Nonetheless, risk assessment is—to this day—confounded by the lack of full comprehension of underlying genetics and modifying genetic risk factors that complicate the yet established genotype-phenotype correlations. Further research that focuses on identifying these additional risk markers is crucial.
Highlights
Aortic aneurysms can be categorised into two subtypes according to anatomical location: abdominal aortic aneurysms (AAAs, below the diaphragm) and thoracic aortic aneurysms (TAAs, above the diaphragm)
In the past decades, gene discovery efforts uncovered a vast number of monogenic disease causes and risk loci involved in TAA pathology of both syndromic and non-syndromic forms
TAA severity and the location of aneurysm formation can differ significantly between phenotypes, urging discrimination by identifying the causal mutation. This is illustrated by Marfan syndrome (MFS) and Loeys–Dietz syndrome (LDS), two connective tissue disorders involving TAA that are assumedly caused by dysregulation of the transforming growth factor-β ligands (TGF-β) pathway—a pathway that is involved in a multitude of cellular functions (Figure 2) [8,9]
Summary
An aortic aneurysm is an abnormal enlargement of the aorta, caused by progressive dilatation of a weakened vascular wall [1]. The location and type of variant in the same gene can influence the risk of aortic dissection: haplo-insufficient (e.g., out-of-frame splice site mutations, premature stopcodons) or dominant negative mutations (e.g., inframe indels and missense mutations) can affect survival rates in a different manner in TAA diseases as demonstrated in the vascular Ehlers–Danlos syndrome [7]. These associations enable clinicians to stratify patients according to risk, establish well-defined clinical guidelines and determine endpoints for surgical intervention. Genetic modifiers and emerging non-genetic risk factors (Figure 1A) will be discussed
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