Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications

Thoracic aortic aneurysms, with an estimated prevalence in the general population of 1%, are potentially lethal, via rupture or dissection. Over the prior two decades, there has been an exponential increase in our understanding of the genetics of thoracic aortic aneurysm and/or dissection (TAAD). To date, 30 genes have been shown to be associated with the development of TAAD and ∼30% of individuals with nonsyndromic familial TAAD have a pathogenic mutation in one of these genes. This review represents the authors' yearly update summarizing the genes associated with TAAD, including implications for the surgical treatment of TAAD. Molecular genetics will continue to revolutionize the approach to patients afflicted with this devastating disease, permitting the application of genetically personalized aortic care.

This review is the update to the 2017 paper "Genes Associated with Thoracic Aortic Aneurysm and Dissection" published in AORTA. 1 We have updated both ►Table 1 listing the genes known to predispose to thoracic aortic aneurysm or dissection (TAAD) and ►Fig. 1, with the recommended sizes for surgical intervention for each specific mutation, based upon published findings in 2017.
Thoracic aortic aneurysms, with an estimated prevalence in the general population of 1%, 2 are potentially lethal, via rupture or dissection. Although significant progress has been made in decreasing the mortality of type A and type B aortic dissections, particularly among individuals who are diagnosed and undergo surgical repair, 3 almost 50% of patients with a type A aortic dissection still die before hospital admission. 4 Therefore, it is critical for clinicians to identify those individuals at risk of TAAD and to perform clinical and genetic risk stratification so that appropriate and personalized management can be provided.
To date, 30 genes have been found to be associated with TAAD (►Table 1 and ►Fig. 1) and $30% of individuals with familial nonsyndromic TAAD (clinical manifestations restricted to the aorta) have a pathogenic variant in one or more of these Table 1 Genes associated with syndromic and nonsyndromic thoracic aortic aneurysm and/or dissection, associated vascular characteristics, and size criteria for elective surgical intervention (SMAD6 is the only gene that has been added to this  It is important to note that since mutations in many of these genes are rare and have only recently been implicated in TAAD, there is a lack of adequate prospective clinical studies. Therefore, it is difficult to establish threshold diameters for intervention for TAAs, and each individual must be considered on a case by case basis, taking into account the rate of change in aneurysm size (> 0.5 cm per year is considered rapid), any family history of aortic dissection at diameters < 5.0 cm, and the presence of significant aortic regurgitation, which are all indications for early repair if present.
A " þ " symbol in the syndromic TAAD column indicates that mutations in the gene have been found in patients with syndromic TAAD (same for the nonsyndromic TAAD column). A "-" symbol in the syndromic TAAD column indicates that mutations in the gene have not been found in patients with syndromic TAAD (same for the nonsyndromic TAAD column).
A reference is provided for each of the associated vascular characteristics not reported in the OMIM entry for that gene. Standard ¼ surgical intervention at 5.0 to 5.5 cm.
Early aortic dissection Ã ¼ dissection at aortic diameters There are no data to set threshold diameters for the surgical intervention for EDS type IV. 38 The Canadian guidelines recommend surgery for aortic root sizes of 4.0 to 5.0 cm and ascending aorta sizes of 4. Park et al recently demonstrated that Col5a2 haploinsufficiency increased the incidence and severity of AAA and led to aortic arch ruptures and dissections in an angiotensin II-induced aneurysm mouse model. 79 In an earlier paper, Park et al illustrated that mice heterozygous for a null allele in Col5a2 exhibited increased aortic compliance and reduced tensile strength compared with wild-type mice. Tgfb3 knockout mice die at birth from cleft palate 70 , but minor differences in the position and curvature of the aortic arches of these mice compared with wild-type mice have been described. 87 genes. 5 Mutations in these genes lead to a spectrum of risk and severity of type A and B aortic dissections, 5 as well as different extra-aortic manifestations. Specific mutations in ACTA2 are estimated to account for 12 to 21% of familial nonsyndromic TAAD, while mutations in syndromic genes (FBN1, TGFBR1, TGFBR2, SMAD3, and TGFB2) are estimated to account for an additional 14% of cases of familial nonsyndromic TAAD. 5 Other genes listed in ►Table 1 are estimated to contribute to 1 to 2% each or less of familial nonsyndromic TAAD. 5 Given that the majority of familial nonsyndromic TAAD cannot be explained by a mutation in one of the known genes associated with TAAD, it is likely that additional genes remain to be identified. Several important genetic findings have been reported during the past year. Using exome sequencing of 441 patients with bicuspid aortic valve and thoracic aortic aneurysm, Gillis et al identified pathogenic mutations in SMAD6 in 11 afflicted individuals, adding to the growing list of genes associated with TAAD. 6 Additionally, in an exome sequencing study of 27 patients with syndromic or familial TAAD (specifically focused on three pairs of first-degree relatives with the same pathogenic TAAD variant but differing phenotypic severity from three independent families), Landis et al found that variants within two genes, ADCK4 and COL15A1, segregated with mild disease severity among thoracic aortic aneurysm patients, offering clues that may help explain the reduced penetrance and variable expression observed in those with TAAD. 7 Lastly, though not introducing a novel association, work by Franken et al on 290 Marfan syndrome (MFS) patients recently expanded our understanding of the genotype-phenotype relationships in TAAD-by demonstrating that among individuals with MFS, those with haploinsufficient mutations in FBN1 have larger aortic root diameters that exhibit a more rapid dilation rate than those with dominant negative mutations. 8 Similarly, De Cario et al found that the presence of certain common polymorphisms in TGFBR1 and TGFBR2 was associated with reduced cardiovascular disease severity among patients with MFS. 9 These studies completed in 2017 illustrate the dynamic nature of the field of TAAD genetics. Through continued investigation and expanded access to genetic testing for affected patients and their family members, whole genome sequencing will undoubtedly continue to add new genes to the roster of causes for familial TAAD. Molecular genetics will continue to revolutionize the approach to patients afflicted with this devastating disease, permitting the application of genetically personalized aortic care. A major challenge in the field remains the lack of functional studies to prove the pathogenicity of identified variants.
We will continue to provide a yearly update and a revised summary table and revised intervention criterion table in AORTA at the end of each calendar year.

Conflict of Interest
The authors declare no conflict of interest related to this manuscript.

Funding
None.