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

Abstract

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.

Keywords

genetics - thoracic aortic aneurysm - thoracic aortic dissection

• References

• 1 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 (01) 11-20
• 2 Verstraeten A, Luyckx I, Loeys B. Aetiology and management of hereditary aortopathy. Nat Rev Cardiol 2017; 14 (04) 197-208
• 3 Mody PS, Wang Y, Geirsson A. , et al. Trends in aortic dissection hospitalizations, interventions, and outcomes among Medicare beneficiaries in the United States, 2000-2011. Circ Cardiovasc Qual Outcomes 2014; 7 (06) 920-928
• 4 Howard DP, Banerjee A, Fairhead JF, Perkins J, Silver LE, Rothwell PM. ; Oxford Vascular Study. Population-based study of incidence and outcome of acute aortic dissection and premorbid risk factor control: 10-year results from the Oxford Vascular Study. Circulation 2013; 127 (20) 2031-2037
• 5 Milewicz DM, Regalado E. Heritable Thoracic Aortic Disease Overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH. , et al., eds. Seattle, WA: GeneReviews(R); 1993
• 6 Gillis E, Kumar AA, Luyckx I. , et al; Mibava Leducq Consortium. Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor. Front Physiol 2017; 8: 400
• 7 Landis BJ, Schubert JA, Lai D. , et al. Exome sequencing identifies candidate genetic modifiers of syndromic and familial thoracic aortic aneurysm severity. J Cardiovasc Transl Res 2017; 10 (04) 423-432
• 8 Franken R, Teixido-Tura G, Brion M. , et al. Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome. Heart 2017; 103 (22) 1795-1799
• 9 De Cario R, Sticchi E, Lucarini L. , et al. Role of TGFBR1 and TGFBR2 genetic variants in Marfan syndrome. J Vasc Surg 2017; S0741-5214(17)31587-2 . Article in Press
• 10 Milewicz DM, Prakash SK, Ramirez F. Therapeutics targeting drivers of thoracic aortic aneurysms and acute aortic dissections: insights from predisposing genes and mouse models. Annu Rev Med 2017; 68: 51-67
• 11 Milewicz D, Hostetler E, Wallace S. , et al. Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino) 2016; 57 (02) 172-177
• 12 Bradley TJ, Bowdin SC, Morel CF, Pyeritz RE. The expanding clinical spectrum of extracardiovascular and cardiovascular manifestations of heritable thoracic aortic aneurysm and dissection. Can J Cardiol 2016; 32 (01) 86-99
• 13 Disabella E, Grasso M, Gambarin FI. , et al. Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2). Heart 2011; 97 (04) 321-326
• 14 Guo DC, Pannu H, Tran-Fadulu V. , et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007; 39 (12) 1488-1493
• 15 Andelfinger G, Loeys B, Dietz H. A decade of discovery in the genetic understanding of thoracic aortic disease. Can J Cardiol 2016; 32 (01) 13-25
• 16 Heegaard AM, Corsi A, Danielsen CC. , et al. Biglycan deficiency causes spontaneous aortic dissection and rupture in mice. Circulation 2007; 115 (21) 2731-2738
• 17 Meester JA, Vandeweyer G, Pintelon I. , et al. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet Med 2017; 19 (04) 386-395
• 18 Schwarze U, Hata R, McKusick VA. , et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet 2004; 74 (05) 917-930
• 19 Smith LB, Hadoke PW, Dyer E. , et al. Haploinsufficiency of the murine Col3a1 locus causes aortic dissection: a novel model of the vascular type of Ehlers-Danlos syndrome. Cardiovasc Res 2011; 90 (01) 182-190
• 20 De Paepe A, Malfait F. The Ehlers-Danlos syndrome, a disorder with many faces. Clin Genet 2012; 82 (01) 1-11
• 21 Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2007; 2: 32
• 22 Erbel R, Aboyans V, Boileau C. , et al; ESC Committee for Practice Guidelines; The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. Eur Heart J 2014; 35 (41) 2873-2926
• 23 Monroe GR, Harakalova M, van der Crabben SN. , et al. Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1. Am J Med Genet A 2015; 167 (06) 1196-1203
• 24 Mehta S, Dhar SU, Birnbaum Y. Common iliac artery aneurysm and spontaneous dissection with contralateral iatrogenic common iliac artery dissection in classic Ehlers-Danlos syndrome. Int J Angiol 2012; 21 (03) 167-170
• 25 Wenstrup RJ, Meyer RA, Lyle JS. , et al. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 2002; 4 (03) 112-117
• 26 Huang J, Davis EC, Chapman SL. , et al. Fibulin-4 deficiency results in ascending aortic aneurysms: a potential link between abnormal smooth muscle cell phenotype and aneurysm progression. Circ Res 2010; 106 (03) 583-592
• 27 Igoucheva O, Alexeev V, Halabi CM. , et al. Fibulin-4 E57K knock-in mice recapitulate cutaneous, vascular and skeletal defects of recessive Cutis Laxa 1B with both elastic fiber and collagen fibril abnormalities. J Biol Chem 2015; 290 (35) 21443-21459
• 28 Jelsig AM, Urban Z, Hucthagowder V, Nissen H, Ousager LB. Novel ELN mutation in a family with supravalvular aortic stenosis and intracranial aneurysm. Eur J Med Genet 2017; 60 (02) 110-113
• 29 Callewaert B, Renard M, Hucthagowder V. , et al. New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. Hum Mutat 2011; 32 (04) 445-455
• 30 Szabo Z, Crepeau MW, Mitchell AL. , et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet 2006; 43 (03) 255-258
• 31 Capuano A, Bucciotti F, Farwell KD. , et al. Diagnostic exome sequencing identifies a novel gene, EMILIN1, associated with autosomal-dominant hereditary connective tissue disease. Hum Mutat 2016; 37 (01) 84-97
• 32 Pereira L, Andrikopoulos K, Tian J. , et al. Targeting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet 1997; 17 (02) 218-222
• 33 Pereira L, Lee SY, Gayraud B. , et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A 1999; 96 (07) 3819-3823
• 34 Judge DP, Biery NJ, Keene DR. , et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 2004; 114 (02) 172-181
• 35 Habashi JP, Judge DP, Holm TM. , et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312 (5770): 117-121
• 36 Lima BL, Santos EJ, Fernandes GR. , et al. A new mouse model for Marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression. PLoS One 2010; 5 (11) e14136
• 37 Morris SA, Orbach DB, Geva T, Singh MN, Gauvreau K, Lacro RV. Increased vertebral artery tortuosity index is associated with adverse outcomes in children and young adults with connective tissue disorders. Circulation 2011; 124 (04) 388-396
• 38 Hiratzka LF, Bakris GL, Beckman JA. , et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American College of Radiology; American Stroke Association; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of Thoracic Surgeons; Society for Vascular Medicine. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. J Am Coll Cardiol 2010; 55 (14) e27-e129
• 39 Takeda N, Morita H, Fujita D. , et al. Congenital contractual arachnodactyly complicated with aortic dilatation and dissection: case report and review of literature. Am J Med Genet A 2015; 167A (10) 2382-2387
• 40 Retailleau K, Arhatte M, Demolombe S. , et al. Smooth muscle filamin A is a major determinant of conduit artery structure and function at the adult stage. Pflugers Arch 2016; 468 (07) 1151-1160
• 41 Feng Y, Chen MH, Moskowitz IP. , et al. Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci U S A 2006; 103 (52) 19836-19841
• 42 Reinstein E, Frentz S, Morgan T. , et al. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in filamin A. Eur J Hum Genet 2013; 21 (05) 494-502
• 43 Lange M, Kasper B, Bohring A. , et al. 47 patients with FLNA associated periventricular nodular heterotopia. Orphanet J Rare Dis 2015; 10: 134
• 44 Kuang SQ, Medina-Martinez O, Guo DC. , et al. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest 2016; 126 (03) 948-961
• 45 Lee VS, Halabi CM, Hoffman EP. , et al; Brigham Genomic Medicine. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A 2016; 113 (31) 8759-8764
• 46 Hornstra IK, Birge S, Starcher B, Bailey AJ, Mecham RP, Shapiro SD. Lysyl oxidase is required for vascular and diaphragmatic development in mice. J Biol Chem 2003; 278 (16) 14387-14393
• 47 Mäki JM, Räsänen J, Tikkanen H. , et al. Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation 2002; 106 (19) 2503-2509
• 48 Ren W, Liu Y, Wang X. , et al. β-Aminopropionitrile monofumarate induces thoracic aortic dissection in C57BL/6 mice. Sci Rep 2016; 6: 28149
• 49 Guo DC, Gong L, Regalado ES. , et al; GenTAC Investigators, National Heart, Lung, and Blood Institute Go Exome Sequencing Project; Montalcino Aortic Consortium. MAT2A mutations predispose individuals to thoracic aortic aneurysms. Am J Hum Genet 2015; 96 (01) 170-177
• 50 Combs MD, Knutsen RH, Broekelmann TJ. , et al. Microfibril-associated glycoprotein 2 (MAGP2) loss of function has pleiotropic effects in vivo. J Biol Chem 2013; 288 (40) 28869-28880
• 51 Bellini C, Wang S, Milewicz DM, Humphrey JD. Myh11(R247C/R247C) mutations increase thoracic aorta vulnerability to intramural damage despite a general biomechanical adaptivity. J Biomech 2015; 48 (01) 113-121
• 52 Pannu H, Tran-Fadulu V, Papke CL. , et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet 2007; 16 (20) 2453-2462
• 53 Wang L, Guo DC, Cao J. , et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet 2010; 87 (05) 701-707
• 54 McKellar SH, Tester DJ, Yagubyan M, Majumdar R, Ackerman MJ, Sundt III TM. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg 2007; 134 (02) 290-296
• 55 Proost D, Vandeweyer G, Meester JA. , et al. Performant mutation identification using targeted next-generation sequencing of 14 thoracic aortic aneurysm genes. Hum Mutat 2015; 36 (08) 808-814
• 56 Guo DC, Regalado E, Casteel DE. , et al; GenTAC Registry Consortium; National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 2013; 93 (02) 398-404
• 57 Doyle AJ, Doyle JJ, Bessling SL. , et al. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 2012; 44 (11) 1249-1254
• 58 Callewaert BL, Willaert A, Kerstjens-Frederikse WS. , et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat 2008; 29 (01) 150-158
• 59 Micha D, Guo DC, Hilhorst-Hofstee Y. , et al. SMAD2 mutations are associated with arterial aneurysms and dissections. Hum Mutat 2015; 36 (12) 1145-1149
• 60 Zhang W, Zeng Q, Xu Y. , et al. Exome sequencing identified a novel SMAD2 mutation in a Chinese family with early onset aortic aneurysms. Clin Chim Acta 2017; 468: 211-214
• 61 Tan CK, Tan EH, Luo B. , et al. SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS. J Am Heart Assoc 2013; 2 (03) e000269
• 62 van der Linde D, van de Laar IM, Bertoli-Avella AM. , et al. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J Am Coll Cardiol 2012; 60 (05) 397-403
• 63 van de Laar IM, van der Linde D, Oei EH. , et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012; 49 (01) 47-57
• 64 Zhang P, Hou S, Chen J. , et al. Smad4 deficiency in smooth muscle cells initiates the formation of aortic aneurysm. Circ Res 2016; 118 (03) 388-399
• 65 Heald B, Rigelsky C, Moran R. , et al. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia due to SMAD4. Am J Med Genet A 2015; 167A [phone]
• 66 Wain KE, Ellingson MS, McDonald J. , et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med 2014; 16 (08) 588-593
• 67 Lindsay ME, Schepers D, Bolar NA. , et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 2012; 44 (08) 922-927
• 68 Boileau C, Guo DC, Hanna N. , et al; National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 2012; 44 (08) 916-921
• 69 Renard M, Callewaert B, Malfait F. , et al. Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2. Int J Cardiol 2013; 165 (03) 584-587
• 70 Bertoli-Avella AM, Gillis E, Morisaki H. , et al. Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol 2015; 65 (13) 1324-1336
• 71 Gallo EM, Loch DC, Habashi JP. , et al. Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest 2014; 124 (01) 448-460
• 72 MacCarrick G, Black III JH, Bowdin S. , et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med 2014; 16 (08) 576-587
• 73 Jondeau G, Ropers J, Regalado E. , et al; Montalcino Aortic Consortium. International Registry of Patients Carrying TGFBR1 or TGFBR2 mutations: results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 2016; 9 (06) 548-558
• 74 Boodhwani M, Andelfinger G, Leipsic J. , et al; Canadian Cardiovascular Society. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol 2014; 30 (06) 577-589
• 75 Attias D, Stheneur C, Roy C. , et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation 2009; 120 (25) 2541-2549
• 76 Teixidó-Tura G, Franken R, Galuppo V. , et al. Heterogeneity of aortic disease severity in patients with Loeys-Dietz syndrome. Heart 2016; 102 (08) 626-632
• 77 Tran-Fadulu V, Pannu H, Kim DH. , et al. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet 2009; 46 (09) 607-613
• 78 Wenstrup RJ, Florer JB, Davidson JM. , et al. Murine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. J Biol Chem 2006; 281 (18) 12888-12895
• 79 Park AC, Phan N, Massoudi D. , et al. Deficits in Col5a2 expression result in novel skin and adipose abnormalities and predisposition to aortic aneurysms and dissections. Am J Pathol 2017; 187 (10) 2300-2311
• 80 Park AC, Phillips CL, Pfeiffer FM. , et al. Homozygosity and heterozygosity for null col5a2 alleles produce embryonic lethality and a novel classic Ehlers-Danlos syndrome-related phenotype. Am J Pathol 2015; 185 (07) 2000-2011
• 81 Kuang SQ, Kwartler CS, Byanova KL. , et al. Rare, nonsynonymous variant in the smooth muscle-specific isoform of myosin heavy chain, MYH11, R247C, alters force generation in the aorta and phenotype of smooth muscle cells. Circ Res 2012; 110 (11) 1411-1422
• 82 Koenig SN, LaHaye S, Feller JD. , et al. Notch1 haploinsufficiency causes ascending aortic aneurysms in mice. JCI Insight 2017; 2 (21) 91353
• 83 Berk M, Desai SY, Heyman HC, Colmenares C. Mice lacking the ski proto-oncogene have defects in neurulation, craniofacial, patterning, and skeletal muscle development. Genes Dev 1997; 11 (16) 2029-2039
• 84 Zoppi N, Chiarelli N, Cinquina V, Ritelli M, Colombi M. GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Hum Mol Genet 2015; 24 (23) 6769-6787
• 85 Cheng CH, Kikuchi T, Chen YH. , et al. Mutations in the SLC2A10 gene cause arterial abnormalities in mice. Cardiovasc Res 2009; 81 (02) 381-388
• 86 Galvin KM, Donovan MJ, Lynch CA. , et al. A role for smad6 in development and homeostasis of the cardiovascular system. Nat Genet 2000; 24 (02) 171-174
• 87 Azhar M, Schultz JJ, Grupp I. , et al. Transforming growth factor beta in cardiovascular development and function. Cytokine Growth Factor Rev 2003; 14 (05) 391-407