State-of-the-Art Review

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AORTA, February 2017, Volume 5, Issue 1:11-20
DOI: 10.12945/j.aorta.2017.17.003

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

Adam J. Brownstein, BA1, Bulat A. Ziganshin, MD1, Helena Kuivaniemi, MD, PhD2, Simon C. Body, MD, MPH3, Allen E. Bale, MD4, John A. Elefteriades, MD1*

1Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut, USA

2Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, and Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa

3Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

4Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA

Abstract

Thoracic aortic aneurysm (TAA) is a lethal disease, with a natural history of enlarging progressively until dissection or rupture occurs. Since the discovery almost 20 years ago that ascending TAAs are highly familial, our understanding of the genetics of thoracic aortic aneurysm and/or dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD; the majority of them encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the TGF-β signaling pathways. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of the TAAD-associated genes, associated clinical features of the vasculature, and implications for surgical treatment of TAAD. With the widespread use of next-generation sequencing and the development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes as well as novel variants within the known TAAD genes will continue to be identified.

Thoracic aortic aneurysms (TAAs), which have an estimated annual incidence of 10.4 per 100,000 people [1], are typically clinically silent yet potentially fatal, as their natural history is to progressively expand until dissection or rupture occurs. Our genetic understanding of thoracic aortic aneurysm and dissection (TAAD) has rapidly advanced since the identification of the FBN1 gene as the cause of Marfan syndrome in 1991 [2] and the discovery of the familial nature of TAAD in the late 1990s. While studies demonstrate that 20% of individuals with non-syndromic TAAD have a positive family history [3, 4], this percentage is most likely a marked underestimation, as not all family members of affected individuals undergo routine aortic imaging [5]. Of the 29 TAAD-associated genes identified to date, the majority encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor (TGF)-β signaling pathway (Table 1) (reviewed in [6-14]). 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 [17-19].

Table 1.

Genes associated with syndromic and non-syndromic thoracic aortic aneurysm and dissection, associated vascular characteristics, and size criteria for elective surgical intervention.

Gene Protein Animal model leading to vascular phenotype? Syndromic TAAD Non-syndromic TAAD Associated disease/syndrome Associated clinical characteristics of the vasculature Ascending aorta size (cm) for surgical intervention Mode of inheritance OMIM
ACTA2 Smooth muscle α-actin No [30] + + AAT6 + multisystemic smooth muscle dysfunction + MYMY5 TAAD, early aortic dissection*, CAD, stroke (moyamoya disease), PDA, pulmonary artery dilation, BAV [6, 9] 4.5-5.0a [10, 31, 32] AD 611788 613834 614042
BGN Biglycan Yes [33] + - Meester-Loeys syndrome ARD, TAAD, pulmonary artery aneurysm, IA, arterial tortuosity [34] Standard X-linked 300989
COL1A2 Collagen 1 α2 chain No + - EDS, arthrochalasia type (VIIb) + cardiac valvular type Borderline aortic root enlargement [9, 35] Standard AD + AR 130060 225320
COL3A1 Collagen 3 α1 chain Yes [36] + - EDS, vascular type (IV) TAAD, early aortic dissection*, visceral arterial dissection, vessel fragility, IA [29, 37, 38] 5.0b [29] AD 130050
COL5A1 Collagen 5 α1 chain Noc + - EDS, classic type (I) ARD, rupture/dissection of medium-sized arteries [39-41] Standard AD 130000
COL5A2 Collagen 5 α2 chain Nod + - EDS, classic type (II) ARD Standard AD 130000
EFEMP2 Fibulin-4 Yes [42, 43] + - Cutis laxa, AR type Ib Ascending aortic aneurysm, other arterial aneurysm, arterial tortuosity and stenosis Standard AR 614437
ELN Elastin No + - Cutis laxa, AD ARD, ascending aortic aneurysm/dissection, BAV, IA possibly associated with SVAS [44-46] Standard AD 123700 185500
EMILIN1 Elastin microfibril interfacer 1 No + - Unidentified CTD Ascending and descending aortic aneurysm [47] Standard AD Unassigned
FBN1 Fibrillin-1 Yes [48-52] + + Marfan syndrome ARD, TAAD, AAA, other arterial aneurysm, pulmonary artery dilatation, arterial tortuosity [53] 5.0 [10, 28] AD 154700
FBN2 Fibrillin-2 No + - Contractural arachnodactyly Rare ARD and aortic dissection [54], BAV, PDA Standard AD 121050
FLNA Filamin A Yes [55, 56] + - Periventricular nodular heterotopia Aortic dilatation/aneurysm, peripheral arterial dilatation [57], PDA, IA [58], BAV Standard XLD 300049
FOXE3 Forkhead box 3 Yes [59] - + AAT11 ARD, TAAD (primarily type A dissection) [59] Standard AD 617349
LOX Lysyl oxidase Yes [6063] - + AAT10 TAAD, AAA, hepatic artery aneurysm, BAV, CAD Standard AD 617168
MAT2A Methionine adenosyltransferase II alpha Noe [64] - + FTAA Thoracic aortic aneurysm, BAV [64] Standard AD Unassigned
MFAP5 Microfibril-associated glycoprotein 2 Partiallyf [65] - + AAT9 ARD, TAAD Standard AD 616166
MYH11 Smooth muscle myosin heavy chain Partiallyg [66] - + AAT4 TAAD, early aortic dissection*, PDA, CAD, peripheral vascular occlusive disease, carotid IA 4.5-5.0 [10, 67] AD 132900
MYLK Myosin light chain kinase Noh [68] - + AAT7 TAAD, early aortic dissection* 4.5-5.0a [10, 68] AD 613780
NOTCH1 NOTCH1 No - + AOVD1 BAV/TAAD [69, 70] Standard AD 109730
PRKG1 Type 1 cGMP-dependent protein kinase No - + AAT8 TAAD, early aortic dissection*, AAA, coronary artery aneurysm/dissection, aortic tortuosity, small vessel CVD 4.5-5.0 [71] AD 615436
SKI Sloan Kettering proto-oncoprotein Noi + - Shprintzen-Goldberg syndrome ARD, arterial tortuosity, pulmonary artery dilation, other (splenic) arterial aneurysm [72] Standard AD 182212
SLC2A10 Glucose transporter 10 Noj + - Arterial tortuosity syndrome ARD [73], ascending aortic aneurysm [73], other arterial aneurysm, arterial tortuosity, elongated arteries, aortic/pulmonary artery stenosis Standard AR 208050
SMAD2 SMAD2 No + - Unidentified CTD with arterial aneurysm/dissection ARD, ascending aortic aneurysm, vertebral/carotid aneurysm/dissection [74] Standard AD Unassigned
SMAD3 SMAD3 Partiallyk [75] + + LDS type 3 ARD, TAAD, early aortic dissection*, AAA, arterial tortuosity, other arterial aneurysm/dissection, IA, BAV [76, 77] 4.0-4.2 [10, 28] AD 613795
SMAD4 SMAD4 Yes [78] + - JP/HHT syndrome ARD, TAAD, AVM, IA [79, 80] Standard AD 175050
TGFB2 TGF-β2 Yes [81] + + LDS type 4 ARD, TAAD, arterial tortuosity, other arterial aneurysm, BAV [81, 82] 4.5-5.0l [83] AD 614816
TGFB3 TGF-β3 Nom + - LDS type 5 ARD, TAAD, AAA/dissection, other arterial aneurysm, IA/dissection [84] Standard AD 615582
TGFBR1 TGF-β receptor type 1 Yes [85] + + LDS type 1 + AAT5 TAAD, early aortic dissection*, AAA, arterial tortuosity, other arterial aneurysm/dissection, IA, PDA, BAV [86] 4.0-4.5n [10, 26, 28] AD 609192
TGFBR2 TGF-β receptor type 2 Yes [78, 85] + + LDS type 2 + AAT3 TAAD, early aortic dissection*, AAA, arterial tortuosity, other arterial aneurysm/dissection, IA, PDA, BAV [86] 4.0-4.5n [10, 26, 28] AD 610168

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.

AAA = abdominal aortic aneurysm; AAT = aortic aneurysm = familial thoracic; AD = autosomal dominant; AOVD = aortic valve disease; AR = autosomal recessive; ARD = aortic root dilatation; AVM = arteriovenous malformation; BAV = bicuspid aortic valve; CAD = coronary artery disease; CTD = connective tissue disease; CVD = cerebrovascular disease; EDS = Ehlers-Danlos syndrome; FTAA = familial thoracic aortic aneurysm; HHT = hereditary hemorrhagic telangiectasia; IA = intracranial aneurysm; JP = juvenile polyposis; LDS = Loeys-Dietz syndrome; MYMY= moyamoya disease; OMIM = Online Mendelian Inheritance in Man; PDA = patent ductus arteriosus; SVAS = supravalvular aortic stenosis; TGF = transforming growth factor; TAAD = thoracic aortic aneurysm and dissection; TGFBR = TGF-β receptor; XLD = X-linked dominant

Standard = surgical intervention at 5.0-5.5 cm

* Early aortic dissection = dissection at aortic diameter < 5.0 cm

a Individuals with MYLK and ACTA2 mutations have been shown to have aortic dissections at a diameter of 4.0 cm [31, 68].

b There are no data to set threshold diameters for surgical intervention for EDS Type IV [28]. The Canadian guidelines recommend surgery for aortic root sizes of 4.0-5.0 cm and ascending aorta sizes of 4.2-5.0 cm, though these patients are at high risk of surgical complications due to poor-quality vascular tissue [87].

c Wenstrup et al. found that mice heterozygous for an inactivating mutation in Col5a1 exhibit decreased aortic compliance and tensile strength relative to wildtype mice [91].

d Park et al. illustrated that mice heterozygous for a null allele in Col5a2 exhibited increased aortic compliance and reduced tensile strength compared to wildtype mice [92].

e Guo et al. found that knockdown of mat2aa in zebrafish led to defective aortic arch development [64].

f Combs et al. demonstrated that Mfap2 and Mfap5 double knockout (Mfap2-/-;Mfap5-/-) mice exhibit age-dependent aortic dilation, though this is not the case with Mfap5 single knockout mice.

g While Kuang et al. reported that a mouse knock-in model (Myh11R247C/R247C) does not lead to a severe vascular phenotype under normal conditions [93], Bellini et al. demonstrated that induced hypertension in this mouse model led to intramural delaminations (separation of aortic wall layers without dissection) or premature deaths (due to aortic dissection based on necroscopy according to unpublished data by Bellini et al.) in over 20% of the R247C mice, accompanied by focal accumulation of glycosaminoglycans within the aortic wall (a typical histological feature of TAAD).

h Wang et al. demonstrated that SMC-specific knockdown of Mylk in mice led to histopathological changes (increased pools of proteoglycans) and altered gene expression consistent with medial degeneration of the aorta, though no aneurysm formation was observed.

i Doyle et al. found that knockdown of paralogs of mammalian SKI in zebrafish led to craniofacial and cardiac anomalies, including failure of cardiac looping and malformations of the outflow tract [72]. Berk et al. showed that mice lacking Ski exhibit craniofacial, skeletal muscle, and central nervous system abnormalities, which are all features of Shprintzen-Goldberg syndrome, but no evidence of aneurysm development was reported [94].

j Mice with homozygous missense mutations in Slc2a10 have not been shown to have the vascular abnormalities seen with arterial tortuosity syndrome [95], though Cheng et al. did demonstrate that such mice do exhibit abnormal elastogenesis within the aortic wall [96].

k Tan et al. demonstrated that Smad3 knockout mice only developed aortic aneurysms with angiotensin II-induced vascular inflammation, though the knockout mice did have medial dissections evident on histological analysis of their aortas and exhibited aortic dilatation relative to wildtype mice prior to angiotensin II infusion [75].

l 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 [97].

n Current U.S. guidelines recommend prophylactic surgery for LDS types 1 and 2 at ascending aortic diameters of 4.0-4.2 cm(10, 28). However, the European guidelines state that more clinical data are required [29]. Patients with TGFBR2 mutations have similar outcomes to patients with FBN1 mutations once their disease is diagnosed(88), and the clinical course of LDS 1 and 2 does not appear to be as severe as originally reported [26, 89, 90]. Therefore, medically treated adult patients with LDS 1 or 2 may not require prophylactic surgery at ascending aortic diameters of 4.0-4.2 cm [6]. Individuals with TGFBR2 mutations are more likely to have aortic dissections at diameters < 5.0 cm than those with TGFBR1 mutations [26, 90]. A more nuanced approach proposed by Jondeau et al. utilizing the presence of TGFBR2 mutations (vs. TGFBR1 mutations), the co-occurrence of severe systemic features (arterial tortuosity, hypertelorism, wide scarring), female gender, low body surface area, and a family history of dissection or rapid aortic root enlargement, which are all risk factors for aortic dissection, may be beneficial for LDS 1 and 2 patients to avoid unnecessary surgery at small aortic diameters [26]. Therefore, in LDS 1 or 2 individuals without the above features, Jondeau et al. maintain that 4.5 cm may be an appropriate threshold, but females with TGFBR2 mutations and severe systemic features may benefit from surgery at 4.0 cm [26].

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 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 [21-27].

Figure 1.

Simplified schematic illustration of ascending aorta dimensions for prophylactic surgical intervention divided by gene category: ECM genes, SMC contractile unit and metabolism genes, and TGF-β signaling pathway genes (data derived from Table 1). ECM, extracellular matrix; LDS, Loeys-Dietz syndrome; MFS, Marfan syndrome; SMC, smooth muscle cell; EDS, Ehlers-Danlos syndrome.

media/vol5/issue1/images/aorta-05-011-g001.jpg

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 management recommendations as they become available.

Acknowledgements

AJB was supported by the Richard K. Gershon, M.D., Student Research Fellowship and the Yale University School of Medicine Medical Student Research Fellowship.

Conflict of Interest

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

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Cite this article as: Brownstein AJ, Ziganshin BA, Kuivaniemi H, Body SC, Bale AE, Elefteriades JA. Genes Associated with Thoracic Aortic Aneurysm and Dissection: An Update and Clinical Implications . AORTA (Stamford). 2017;5(1):11-20. DOI: 10.12945/j.aorta.2017.17.003

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