Genes Associated with Thoracic Aortic Aneurysm and Dissection An Update and Clinical Implications

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It is important to note that as mutations in many of these genes are rare and have only recently been implicated in TAAD, there are a lack of adequate prospective clinical studies. Therefore, it is difficult to establish threshold diameters for intervention for TAA, 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) and any family history of aortic dissection.
A "+" symbol in the syndromic or non-syndromic TAAD column indicates that mutations in the gene have been found in patients with syndromic or non-syndromic TAAD, respectively. A "-" symbol in the syndromic or non-syndromic TAAD column indicates that mutations in the gene have not been found in patients with syndromic or non-syndromic TAAD, respectively. A reference is provided for each of the associated vascular characteristics not reported in the OMIM entry for that gene.   There are limited data concerning the timing of surgical intervention for LDS type 4. However, there has been a case of a Type A aortic dissection at an aortic diameter < 5.0 cm [83], hence the recommended threshold range of 4.5-5.0 cm. m Tgfb3 knockout mice die at birth from cleft palate [84], but minor differences in the position and curvature of the aortic arches of these mice compared to wildtype mice have been described [ non-syndromic TAAD [6]. The identification of specific mutated genes in patients with TAAD is crucial because it permits targeted genetic testing of apparently unaffected but currently undiagnosed family members. Furthermore, genetic information helps determine the patient's risk for aortic dissection and rupture, especially mutations associated with vascular events at an ascending aorta size < 5.0 cm (Figure 1), which does not usually necessitate aortic resection in the absence of such mutations, a family history of aortic dissection, or rapid aneurysmal growth (> 0.5 cm/year). Identification of specific genetic variants associated with TAAD clinical outcomes may help predict how aortic disease will manifest and estimate the risk of other vascular diseases [6] (Table 1). Moreover, genotype-phenotype correlations have been established for both syndromic (FBN1, COL3A1, TGFBR1, and TGFBR2) and non-syndromic (ACTA2) TAAD, meaning that the specific genetic variant in TAAD-affected individuals can help predict the course and severity of disease [21][22][23][24][25][26][27].
metabolism, or the transforming growth factor (TG-F)-β signaling pathway (Table 1) (reviewed in [6][7][8][9][10][11][12][13][14]). Almost one-quarter of patients with TAAD possess a mutation in one of these genes [6], the majority of which are inherited in an autosomal dominant fashion with reduced penetrance and variable expressivity [15,16]. It is of interest to note that most genetic risk factors for aneurysms in other locations of the body (e.g., in intracranial arteries or the abdominal aorta) are different from those for TAAD [17][18][19]. TAAD has been classified into syndromic (associated with abnormalities of other organ systems) and non-syndromic (manifestations restricted to the aorta) [12,20] categories, yet there is significant overlap in the genetic basis of syndromic and non-syndromic familial TAAD. Mutations in FBN1 and Loeys-Dietz syndrome (LDS) type 1-4 genes (TGFBR1, TGFBR2, SMAD3, and TGFB2) are estimated to account for 10% of familial non-syndromic TAAD [6]. Also, mutations in ACTA2 are estimated to cause 12-21% of familial TAAD, whereas mutations in other genes may each account for only 1-2% or less of

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The authors have no conflict of interest relevant to this publication.

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As stated in the most recent United States and European guidelines [28,29], personalized care based on underlying genetic mutations is and will continue to be a critical aspect of high-quality patient care. As genetic testing becomes more widespread, individuals at genetic risk for TAAD may be identified earlier so that prophylactic medical and surgical intervention can be implemented to avert potentially fatal complications of TAAD. Furthermore, the utilization of next-generation sequencing could lead to the development of a comprehensive library of pathogenic genetic variants. As the genetic basis of TAAD is still a highly dynamic and burgeoning field, we present the most up-to-date list of genes associated with TAAD (Table 1). We plan to update this report annually, adding new genes, intervention criteria, and manage-