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 table since publication of our 2017 AORTA review paper.).
| Gene | Protein | Animal model leading to vascular phenotype? | Syndromic TAAD | Nonsyndromic FTAAD | 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 | Yes 10 | + | + | AAT6 + multisystemic smooth muscle dysfunction + MYMY5 | TAAD, early aortic dissection,* CAD, stroke (moyamoya disease), PDA, pulmonary artery dilation, BAV 11 12 | 4.5–5.0 a 13 14 15 | AD | 611788 613834 614042 |
| BGN | Biglycan | Yes 16 | + | − | Meester-Loeys syndrome | ARD, TAAD, pulmonary artery aneurysm, IA, arterial tortuosity 17 | Standard | X-linked | 300989 |
| COL1A2 | Collagen 1 α2 chain | No | + | − | EDS, arthrochalasia type (VIIb) + cardiac valvular type | Borderline aortic root enlargement 12 18 | Standard | AD + AR | 130060 225320 |
| COL3A1 | Collagen 3 α1 chain | Yes 19 | + | − | EDS, vascular type (IV) | TAAD, early aortic dissection,* visceral arterial dissection, vessel fragility, IA 20 21 22 | 5.0 b 22 | AD | 130050 |
| COL5A1 | Collagen 5 α1 chain | No e | + | − | EDS, classic type 1 | ARD, rupture/dissection of medium sized arteries 23 24 25 | Standard | AD | 130000 |
| COL5A2 | Collagen 5 α2 chain | Partially f | + | − | EDS, classic type 2 | ARD | Standard | AD | 130000 |
| EFEMP2 | Fibulin-4 | Yes 26 27 | + | − | Cutis laxa, AR type Ib | Ascending aortic aneurysms, other arterial aneurysms, arterial tortuosity and stenosis | Standard | AR | 614437 |
| ELN | Elastin | No | + | − | Cutis laxa, AD | ARD, ascending aortic aneurysm and dissection, BAV, IA possibly associated with SVAS 28 29 30 | Standard | AD | 123700 185500 |
| EMILIN1 | Elastin microfibril interfacer 1 | No | + | − | Unidentified CTD | Ascending and descending aortic aneurysm 31 | Standard | AD | Unassigned |
| FBN1 | Fibrillin-1 | Yes 32 33 34 35 36 | + | + | Marfan syndrome | ARD, TAAD, AAA, other arterial aneurysms, pulmonary artery dilatation, arterial tortuosity 37 | 5.0 15 38 | AD | 154700 |
| FBN2 | Fibrillin-2 | No | + | − | Contractual arachnodactyly | Rare ARD and aortic dissection, 39 BAV, PDA | Standard | AD | 121050 |
| FLNA | Filamin A | Yes 40 41 | + | − | Periventricular nodular heterotopia | Aortic dilatation/aneurysms, peripheral arterial dilatation, 42 PDA, IA, 43 BAV | Standard | XLD | 300049 |
| FOXE3 | Forkhead box 3 | Yes 44 | − | + | AAT11 | TAAD (primarily Type A dissection) 44 | Standard | AD | 617349 |
| LOX | Lysyl oxidase | Yes 45 46 47 48 | − | + | AAT10 | TAAD, AAA, hepatic artery aneurysm, BAV, CAD | Standard | AD | 617168 |
| MAT2A | Methionine adenosyltransferase II α | No g 49 | − | + | FTAA | Thoracic aortic aneurysms, BAV 49 | Standard | AD | Unassigned |
| MFAP5 | Microfibril-associated glycoprotein 2 | Partially h 50 | − | + | AAT9 | ARD, TAAD | Standard | AD | 616166 |
| MYH11 | Smooth muscle myosin heavy chain | Partially i 51 | − | + | AAT4 | TAAD, early aortic dissection,* PDA, CAD, peripheral vascular occlusive disease, carotid IA | 4.5–5.0 15 52 | AD | 132900 |
| MYLK | Myosin light chain kinase | No j 53 | − | + | AAT7 | TAAD, early aortic dissections* | 4.5–5.0 a 15 53 | AD | 613780 |
| NOTCH1 | NOTCH1 | Partially k | − | + | AOVD1 | BAV/TAAD 54 55 | 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 56 | AD | 615436 |
| SKI | Sloan Kettering proto-oncoprotein | No l | + | − | Shprintzen–Goldberg syndrome | ARD, arterial tortuosity, pulmonary artery dilation, other (splenic) arterial aneurysms 57 | Standard | AD | 182212 |
| SLC2A10 | Glucose transporter 10 | No m | + | − | Arterial tortuosity syndrome | ARD, 58 ascending aortic aneurysms, 58 other arterial aneurysms, arterial tortuosity, elongated arteries aortic/pulmonary artery stenosis | Standard | AR | 208050 |
| SMAD2 | SMAD2 | No | + | − | Unidentified CTD with arterial aneurysm/dissections | ARD, ascending aortic aneurysms, vertebral/carotid aneurysms and dissections, AAA 59 60 | Standard | AD | Unassigned |
| SMAD3 | SMAD3 | Partially n 61 | + | + | LDS type 3 | ARD, TAAD, early aortic dissection,* AAA, arterial tortuosity, other arterial aneurysms/dissections, IA, BAV 62 63 | 4.0–4.2 15 38 | AD | 613795 |
| SMAD4 | SMAD4 | Yes 64 | + | − | JP/HHT syndrome | ARD, TAAD, AVMs, IA 65 66 | Standard | AD | 175050 |
| SMAD6 | SMAD6 | No o | − | + | AOV2 | BAV/TAA 6 | Standard | AD | 602931 |
| TGFB2 | TGF-β2 | Yes 67 | + | + | LDS type 4 | ARD, TAAD, arterial tortuosity, other arterial aneurysms, BAV 67 68 | 4.5–5.0 c 69 | AD | 614816 |
| TGFB3 | TGF-β3 | No p | + | − | LDS type 5 | ARD, TAAD, AAA/dissection, other arterial aneurysms, IA/dissection 70 | Standard | AD | 615582 |
| TGFBR1 | TGF-β receptor type 1 | Yes 71 | + | + | LDS type 1 + AAT5 | TAAD, early aortic dissection,* AAA, arterial tortuosity, other arterial aneurysms/dissection, IA, PDA, BAV 72 | 4.0–4.5 d, 15 38 73 | AD | 609192 |
| TGFBR2 | TGF-β receptor type 2 | Yes 64 71 | + | + | LDS type 2 + AAT3 | TAAD, early aortic dissection,* AAA, arterial tortuosity, other arterial aneurysms/dissection, IA, PDA, BAV 72 | 4.0–4.5 d 15 38 73 | AD | 610168 |
Abbreviations: 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; FTAAD, familial thoracic aortic aneurysm and/or dissection; 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/or dissection; TGFBR, TGF-β receptor; XLD, X-linked dominant
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 “ + ” 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 = surgical intervention at 5.0 to 5.5 cm.
Early aortic dissection* = dissection at aortic diameters < 5.0 cm.
Individuals with MYLK and ACTA2 mutations have been shown to have aortic dissections at a diameter of 4.0 cm. 13 53
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 4.2 to 5.0 cm, though these patients are at high risk of surgical complications due to poor-quality vascular tissue. 74
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 69 hence, the recommended threshold range of 4.5 to 5.0 cm.
Current US guidelines recommend prophylactic surgery for LDS types 1 and 2 at ascending aortic diameters of 4.0 to 4.2 cm. 15 38 However, the European guidelines state that more clinical data are required. 22 Patients with TGFBR2 mutations have similar outcomes to patients with FBN1 mutations once their disease is diagnosed, 75 and the clinical course of LDS 1 and 2 does not appear to be as severe as originally reported. 73 76 77 Therefore, medically treated adult patients with LDS 1 or 2 may not require prophylactic surgery at ascending aortic diameters of 4.0 to 4.2 cm. 11 Individuals with TGFBR2 mutations are more likely to have aortic dissections at diameters < 5.0 cm than those with TGFBR1 mutations. 73 77 A more nuanced approach proposed by Jondeau et al utilizing the presence of TGFBR2 mutations (versus 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. 73 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. 73
Wenstrup et al found that mice heterozygous for an inactivating mutation in Col5a1 exhibit decreased aortic compliance and tensile strength relative to wild-type mice. 78
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. 80
Guo et al found that knockdown of mat2aa in zebrafish led to defective aortic arch development. 49
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.
While Kuang et al reported that a mouse knock-in model (Myh11 R247C/R247C ) does not lead to a severe vascular phenotype under normal conditions, 81 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).
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.
Koenig et el recently found that Notch1 haploinsufficiency exacerbates the aneurysmal aortic root dilation in a mouse model of Marfan syndrome and that Notch1 heterozygous mice exhibited aortic root dilation, abnormal smooth muscle cell morphology, and reduced elastic laminae. 82
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. 57 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. 83
Mice with homozygous missense mutations in Slc2a10 have not been shown to have the vascular abnormalities seen with arterial tortuosity syndrome, 84 though Cheng et al did demonstrate that such mice do exhibit abnormal elastogenesis within the aortic wall. 85
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 wild-type mice prior to angiotensin II infusion. 61
Galvin et al demonstrated that Madh6, which encodes Smad6, mutant mice exhibited defects in cardiac valve formation, outflow tract septation, vascular tone, and ossification but no aneurysm development was observed. 86