CC BY 4.0 · Aorta (Stamford) 2017; 05(01): 11-20
DOI: 10.12945/j.aorta.2017.17.003
State-of-the-Art Review
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genes Associated with Thoracic Aortic Aneurysm and Dissection

An Update and Clinical Implications
Adam J. Brownstein
1   Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut, USA
Bulat A. Ziganshin
1   Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut, USA
Helena Kuivaniemi
2   Division 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
Simon C. Body
3   Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Allen E. Bale
4   Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA
John A. Elefteriades
1   Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, Connecticut, USA
› Author Affiliations
Further Information

Publication History

06 January 2017

06 January 2017

Publication Date:
24 September 2018 (online)


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 dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD, the majority of which encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor-β signaling pathway. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of 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 development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes and variants within the genes will continue to be identified.

  • References

  • 1 Ramanath VS, Oh JK, Sundt 3rd TM, Eagle KA. Acute aortic syndromes and thoracic aortic aneurysm. Mayo Clinic Proc 2009; 84: 465-481 . DOI: 10.1016/S0025-6196(11)60566-1
  • 2 Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM. , et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991; 352: 337-339 . DOI: 10.1038/352337a0
  • 3 Biddinger A, Rocklin M, Coselli J, Milewicz DM. Familial thoracic aortic dilatations and dissections: a case control study. J Vasc Surg 1997; 25: 506-511 . DOI: 10.1016/S0741-5214(97)70261-1
  • 4 Coady MA, Davies RR, Roberts M, Goldstein LJ, Rogalski MJ, Rizzo JA. , et al. Familial patterns of thoracic aortic aneurysms. Arch Surg 1999; 134: 361-367 . DOI: 10.1001/archsurg.134.4.361
  • 5 Elefteriades JA, Farkas EA. Thoracic aortic aneurysm clinically pertinent controversies and uncertainties. J Am Coll Card 2010; 55: 841-857 . DOI: 10.1016/j.jacc.2009.08.084
  • 6 Milewicz D, Hostetler E, Wallace S, Mellor-Crummey L, Gong L, Pannu H. , 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: 172-177 . PMID: 26837258
  • 7 Karimi A, Milewicz DM. Structure of the elastin-contractile units in the thoracic aorta and how genes that cause thoracic aortic aneurysms and dissections disrupt this structure. Can J Cardiol 2016; 32: 26-34 . DOI: 10.1016/j.cjca.2015.11.004
  • 8 Isselbacher EM, Lino Cardenas CL, Lindsay ME. Hereditary influence in thoracic aortic aneurysm and dissection. Circulation 2016; 133: 2516-2528 . DOI: 10.1161/CIRCULATIONAHA.116.009762
  • 9 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: 86-99 . DOI: 10.1016/j.cjca.2015.11.007
  • 10 Andelfinger G, Loeys B, Dietz H. A decade of discovery in the genetic understanding of thoracic aortic disease. Can J Cardiol 2016; 32: 13-25 . DOI: 10.1016/j.cjca.2015.10.017
  • 11 Luyckx I, Loeys BL. The genetic architecture of non-syndromic thoracic aortic aneurysm. Heart 2015; 101: 1678-1684 . DOI: 10.1136/heartjnl-2014-306381
  • 12 Pomianowski P, Elefteriades JA. The genetics and genomics of thoracic aortic disease. Ann Cardiothorac Surg 2013; 2: 271-279 . DOI: 10.3978/j.issn.2225-319X.2013.05.12
  • 13 Gillis E, Van Laer L, Loeys BL. Genetics of thoracic aortic aneurysm: at the crossroad of transforming growth factor-beta signaling and vascular smooth muscle cell contractility. Circ Res 2013; 113: 327-340 . DOI: 10.1161/CIRCRESAHA.113.300675
  • 14 Elefteriades JA, Pomianowski P. Practical genetics of thoracic aortic aneurysm. Prog Cardiovasc Dis 2013; 56: 57-67 . DOI: 10.1016/j.pcad.2013.06.002
  • 15 Albornoz G, Coady MA, Roberts M, Davies RR, Tranquilli M, Rizzo JA. , et al. Familial thoracic aortic aneurysms and dissections - Incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg 2006; 82: 1400-1406 . DOI: 10.1016/j.athoracsur.2006.04.098
  • 16 Milewicz DM, Chen H, Park ES, Petty EM, Zaghi H, Shashidhar G. , et al. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections. Am J Cardiol 1998; 82: 474-479 . DOI: 10.1016/S0002-9149(98)00364-6
  • 17 Kuivaniemi H, Ryer EJ, Elmore JR, Tromp G. Understanding the pathogenesis of abdominal aortic aneurysms. Expert Rev Cardiovasc Ther 2015; 13: 975-987 . DOI: 10.1586/14779072.2015.1074861
  • 18 Tromp G, Weinsheimer S, Ronkainen A, Kuivaniemi H. Molecular basis and genetic predisposition to intracranial aneurysm. Ann Med 2014; 46: 597-606 . DOI: 10.3109/07853890.2014.949299
  • 19 Jones GT, Tromp G, Kuivaniemi H, Gretarsdottir S, Baas AF, Giusti B. , et al. Meta-analysis of genome-wide association studies for abdominal aortic aneurysm identifies four new disease-specific risk loci. Circ Res 2017; 120: 341-353 . DOI: 10.1161/CIRCRESAHA.116.308765
  • 20 El-Hamamsy I, Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol 2009; 6: 771-786 . DOI: 10.1038/nrcardio.2009.191
  • 21 Franken R, Groenink M, de Waard V, Feenstra HM, Scholte AJ, van den Berg MP. , et al. Genotype impacts survival in Marfan syndrome. Eur Heart J 2016; 37: 3285-3290 . DOI: 10.1093/eurheartj/ehv739
  • 22 Baudhuin LM, Kotzer KE, Lagerstedt SA. Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants. J Hum Genet 2015; 60: 241-252 . DOI: 10.1038/jhg.2015.10
  • 23 Frank M, Albuisson J, Ranque B, Golmard L, Mazzella JM, Bal-Theoleyre L. , et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet 2015; 23: 1657-1664 . DOI: 10.1038/ejhg.2015.32
  • 24 Shalhub S, Black 3rd JH, Cecchi AC, Xu Z, Griswold BF, Safi HJ. , et al. Molecular diagnosis in vascular Ehlers-Danlos syndrome predicts pattern of arterial involvement and outcomes. J Vasc Surg 2014; 60: 160-169 . DOI: 10.1016/j.jvs.2014.01.070
  • 25 Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med 2014; 16: 881-888 . DOI: 10.1038/gim.2014.72
  • 26 Jondeau G, Ropers J, Regalado E, Braverman A, Evangelista A, Teixedo G. , et al. International registry of patients carrying TGFBR1 or TGFBR2 mutations: results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 2016; 9: 548-558 . DOI: 10.1161/CIRCGENETICS.116.001485
  • 27 Regalado ES, Guo DC, Prakash S, Bensend TA, Flynn K, Estrera A. , et al. Aortic disease presentation and outcome associated with ACTA2 mutations. Circ Cardiovasc Genet 2015; 8: 457-464 . DOI: 10.1161/CIRCGENETICS.114.000943
  • 28 Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey Jr DE. , et al. 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 Card 2010; 55: e27-e129 . DOI: 10.1016/j.jacc.2010.02.015
  • 29 Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H. , et al. 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. The Task Force for the diagnosis and treatment of aortic diseases of the European Society of Cardiology (ESC). Eur Heart J 2014; 35: 2873-2926 . DOI: 10.1093/eurheartj/ehu281
  • 30 Schildmeyer LA, Braun R, Taffet G, Debiasi M, Burns AE, Bradley A. , et al. Impaired vascular contractility and blood pressure homeostasis in the smooth muscle alpha-actin null mouse. FASEB J 2000; 14: 2213-2220 . DOI: 10.1096/fj.99-0927com
  • 31 Disabella E, Grasso M, Gambarin FI, Narula N, Dore R, Favalli V. , et al. Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2). Heart 2011; 97: 321-326 . DOI: 10.1136/hrt.2010.204388
  • 32 Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N. , et al. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 2007; 39: 1488-1493 . DOI: 10.1038/ng.2007.6
  • 33 Heegaard AM, Corsi A, Danielsen CC, Nielsen KL, Jorgensen HL, Riminucci M. , et al. Biglycan deficiency causes spontaneous aortic dissection and rupture in mice. Circulation 2007; 115: 2731-2738 . DOI: 10.1161/CIRCULATIONAHA.106.653980
  • 34 Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L, De Belder S. , 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: 386-395 . DOI: 10.1038/gim.2016.126
  • 35 Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE. , et al. Rare autosomal rec[{AU: Please confirm or correct the conflict of interest statement. }]essive 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: 917-930 . DOI: 10.1086/420794
  • 36 Smith LB, Hadoke PW, Dyer E, Denvir MA, Brownstein D, Miller 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: 182-190 . DOI: 10.1093/cvr/cvq356
  • 37 De Paepe A, Malfait F. The Ehlers-Danlos syndrome, a disorder with many faces. Clin Genet 2012; 82: 1-11 . DOI: 10.1111/j.1399-0004.2012.01858.x
  • 38 Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2007; 2: 32 . DOI: 10.1186/1750-1172-2-32
  • 39 Monroe GR, Harakalova M, van der Crabben SN, Majoor-Krakauer D, Bertoli-Avella AM, Moll FL. , et al. Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1. Am J Med Genet A 2015; 167: 1196-1203 . DOI: 10.1002/ajmg.a.36997
  • 40 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: 167-170 . DOI: 10.1055/s-0032-1325118
  • 41 Wenstrup RJ, Meyer RA, Lyle JS, Hoechstetter L, Rose PS, Levy HP. , et al. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med 2002; 4: 112-117 . DOI: 10.1097/00125817-200205000-00003
  • 42 Huang J, Davis EC, Chapman SL, Budatha M, Marmorstein LY, Word RA. , 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: 583-592 . DOI: 10.1161/CIRCRESAHA.109.207852
  • 43 Igoucheva O, Alexeev V, Halabi CM, Adams SM, Stoilov I, Sasaki T. , 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: 21443-21459 . DOI: 10.1074/jbc.M115.640425
  • 44 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: 110-113 . DOI: 10.1016/j.ejmg.2016.11.004
  • 45 Callewaert B, Renard M, Hucthagowder V, Albrecht B, Hausser I, Blair E. , et al. New insights into the pathogenesis of autosomal-dominant cutis laxa with report of five ELN mutations. Hum Mutat 2011; 32: 445-455 . DOI: 10.1002/humu.21462
  • 46 Szabo Z, Crepeau MW, Mitchell AL, Stephan MJ, Puntel RA, Yin Loke K. , et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet 2006; 43: 255-258 . DOI: 10.1136/jmg.2005.034157
  • 47 Capuano A, Bucciotti F, Farwell KD, Tippin DB, Mroske C, Hulick PJ. , et al. Diagnostic exome sequencing identifies a novel gene, EMILIN1, associated with autosomal-dominant hereditary connective tissue disease. Hum Mutat 2016; 37: 84-97 . DOI: 10.1002/humu.22920
  • 48 Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono R. , et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet 1997; 17: 218-222 . DOI: 10.1038/ng1097-218
  • 49 Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T. , et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 1999; 96: 3819-3823 . DOI: 10.1073/pnas.96.7.3819
  • 50 Judge DP, Biery NJ, Keene DR, Geubtner J, Myers L, Huso DL. , et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 2004; 114: 172-181 . DOI: 10.1172/JCI20641
  • 51 Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK. , et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006; 312: 117-1121 . DOI: 10.1126/science.1124287
  • 52 Lima BL, Santos EJ, Fernandes GR, Merkel C, Mello MR, Gomes JP. , 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: e14136 . DOI: 10.1371/journal.pone.0014136
  • 53 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: 388-396 . DOI: 10.1161/CIRCULATIONAHA.110.990549
  • 54 Takeda N, Morita H, Fujita D, Inuzuka R, Taniguchi Y, Imai Y. , et al. Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: case report and review of literature. Am J Med Genet A 2015; 167A: 2382-2387 . DOI: 10.1002/ajmg.a.37162
  • 55 Retailleau K, Arhatte M, Demolombe S, Jodar M, Baudrie V, Offermanns 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: 1151-1160 . DOI: 10.1007/s00424-016-1813-x
  • 56 Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F. , et al. Filamin A (FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci USA 2006; 103: 19836-19841 . DOI: 10.1073/pnas.0609628104
  • 57 Reinstein E, Frentz S, Morgan T, García-Miñaúr S, Leventer RJ, McGillivray G. , 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: 494-502 . DOI: 10.1038/ejhg.2012.209
  • 58 Lange M, Kasper B, Bohring A, Rutsch F, Kluger G, Hoffjan S. , et al. 47 patients with FLNA associated periventricular nodular heterotopia. Orphanet J Rare Dis 2015; 10: 134 . DOI: 10.1186/s13023-015-0331-9
  • 59 Kuang SQ, Medina-Martinez O, Guo DC, Gong L, Regalado ES, Reynolds CL. , et al. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest 2016; 126: 948-961 . DOI: 10.1172/JCI83778
  • 60 Lee VS, Halabi CM, Hoffman EP, Carmichael N, Leshchiner I, Lian CG. , et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci USA 2016; 113: 8759-8764 . DOI: 10.1073/pnas.1601442113
  • 61 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: 14387-14393 . DOI: 10.1074/jbc.M210144200
  • 62 Maki JM, Rasanen J, Tikkanen H, Sormunen R, Makikallio K, Kivirikko KI. , et al. Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation 2002; 106: 2503-2509 . DOI: 10.1161/01.CIR.0000038109.84500.1E
  • 63 Ren W, Liu Y, Wang X, Jia L, Piao C, Lan F. , et al. β-Aminopropionitrile monofumarate induces thoracic aortic dissection in C57BL/6 mice. Sci Rep 2016; 6: 28149 . DOI: 10.1038/srep28149
  • 64 Guo DC, Gong L, Regalado ES, Santos-Cortez RL, Zhao R, Cai B. , et al. MAT2A mutations predispose individuals to thoracic aortic aneurysms. Am J Hum Genet 2015; 96: 170-177 . DOI: 10.1016/j.ajhg.2014.11.015
  • 65 Combs MD, Knutsen RH, Broekelmann TJ, Toennies HM, Brett TJ, Miller CA. , et al. Microfibril-associated glycoprotein 2 (MAGP2) loss of function has pleiotropic effects in vivo. J Biol Chem 2013; 288: 28869-28880 . DOI: 10.1074/jbc.M113.497727
  • 66 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: 113-121 . DOI: 10.1016/j.jbiomech.2014.10.031
  • 67 Pannu H, Tran-Fadulu V, Papke CL, Scherer S, Liu Y, Presley C. , 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: 2453-2462 . DOI: 10.1093/hmg/ddm201
  • 68 Wang L, Guo DC, Cao J, Gong L, Kamm KE, Regalado E. , et al. Mutations in myosin light chain kinase cause familial aortic dissections. Am J Hum Genet 2010; 87: 701-707 . DOI: 10.1016/j.ajhg.2010.10.006
  • 69 McKellar SH, Tester DJ, Yagubyan M, Majumdar R, Ackerman MJ, Sundt 3rd TM. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. J Thorac Cardiovasc Surg 2007; 134: 290-296 . DOI: 10.1016/j.jtcvs.2007.02.041
  • 70 Proost D, Vandeweyer G, Meester JA, Salemink S, Kempers M, Ingram C. , et al. Performant mutation identification using targeted next-generation sequencing of 14 thoracic aortic aneurysm genes. Hum Mutat 2015; 36: 808-814 . DOI: 10.1002/humu.22802
  • 71 Guo DC, Regalado E, Casteel DE, Santos-Cortez RL, Gong L, Kim JJ. , et al. Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 2013; 93: 398-404 . DOI: 10.1016/j.ajhg.2013.06.019
  • 72 Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D. , et al. Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet 2012; 44: 1249-1254 . DOI: 10.1038/ng.2421
  • 73 Callewaert BL, Willaert A, Kerstjens-Frederikse WS, De Backer J, Devriendt K, Albrecht B. , et al. Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families. Hum Mutat 2008; 29: 150-158 . DOI: 10.1002/humu.20623
  • 74 Micha D, Guo DC, Hilhorst-Hofstee Y, van Kooten F, Atmaja D, Overwater E. , et al. SMAD2 mutations are associated with arterial aneurysms and dissections. Hum Mutat 2015; 36: 1145-1149 . DOI: 10.1002/humu.22854
  • 75 Tan CK, Tan EH, Luo B, Huang CL, Loo JS, Choong C. , et al. SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS. J Am Heart Assoc 2013; 2: e000269 . DOI: 10.1161/JAHA.113.000269
  • 76 van der Linde D, van de Laar IM, Bertoli-Avella AM, Oldenburg RA, Bekkers JA, Mattace-Raso FU. , et al. Aggressive cardiovascular phenotype of aneurysms-osteoarthritis syndrome caused by pathogenic SMAD3 variants. J Am Coll Cardiol 2012; 60: 397-403 . DOI: 10.1016/j.jacc.2011.12.052
  • 77 van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM. , et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012; 49: 47-57 . DOI: 10.1136/jmedgenet-2011-100382
  • 78 Zhang P, Hou S, Chen J, Zhang J, Lin F, Ju R. , et al. SMAD4 deficiency in smooth muscle cells initiates the formation of aortic aneurysm. Circ Res 2016; 118: 388-399 . DOI: 10.1161/CIRCRESAHA.115.308040
  • 79 Heald B, Rigelsky C, Moran R, LaGuardia L, O’Malley M, Burke CA. , 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: 1758-1762 . DOI: 10.1002/ajmg.a.37093
  • 80 Wain KE, Ellingson MS, McDonald J, Gammon A, Roberts M, Pichurin P. , et al. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med 2014; 16: 588-593 . DOI: 10.1038/gim.2014.5
  • 81 Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J. , et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet 2012; 44: 922-927 . DOI: 10.1038/ng.2349
  • 82 Boileau C, Guo DC, Hanna N, Regalado ES, Detaint D, Gong L. , et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet 2012; 44: 916-921 . DOI: 10.1038/ng.2348
  • 83 Renard M, Callewaert B, Malfait F, Campens L, Sharif S, del Campo M. , et al. Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2. Int J Card 2013; 165: 584-587 . DOI: 10.1016/j.ijcard.2012.09.029
  • 84 Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G. , et al. Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol 2015; 65: 1324-1336 . DOI: 10.1016/j.jacc.2015.01.040
  • 85 Gallo EM, Loch DC, Habashi JP, Calderon JF, Chen Y, Bedja D. , et al. Angiotensin II-dependent TGF-beta signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest 2014; 124: 448-460 . DOI: 10.1172/JCI69666
  • 86 MacCarrick G, Black 3rd JH, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL. , et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med 2014; 16: 576-587 . DOI: 10.1038/gim.2014.11
  • 87 Boodhwani M, Andelfinger G, Leipsic J, Lindsay T, McMurtry MS, Therrien J. , et al. Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. Can J Cardiol 2014; 30: 577-589 . DOI: 10.1016/j.cjca.2014.02.018
  • 88 Attias D, Stheneur C, Roy C, Collod-Beroud G, Detaint D, Faivre L. , et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circulation 2009; 120: 2541-2549 . DOI: 10.1161/CIRCULATIONAHA.109.887042
  • 89 Teixido-Tura G, Franken R, Galuppo V, Gutierrez Garcia-Moreno L, Borregan M, Mulder BJ. , et al. Heterogeneity of aortic disease severity in patients with Loeys-Dietz syndrome. Heart 2016; 102: 626-632 . DOI: 10.1136/heartjnl-2015-308535
  • 90 Tran-Fadulu V, Pannu H, Kim DH, Vick 3rd GW, Lonsford CM, Lafont AL. , et al. Analysis of multigenerational families with thoracic aortic aneurysms and dissections due to TGFBR1 or TGFBR2 mutations. J Med Genet 2009; 46: 607-613 . DOI: 10.1136/jmg.2008.062844
  • 91 Wenstrup RJ, Florer JB, Davidson JM, Phillips CL, Pfeiffer BJ, Menezes DW. , et al. Murine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. J Biol Chem 2006; 281: 12888-12895 . DOI: 10.1074/jbc.M511528200
  • 92 Park AC, Phillips CL, Pfeiffer FM, Roenneburg DA, Kernien JF, Adams SM. , 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: 2000-2011 . DOI: 10.1016/j.ajpath.2015.03.022
  • 93 Kuang SQ, Kwartler CS, Byanova KL, Pham J, Gong L, Prakash SK. , 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: 1411-1422 . DOI: 10.1161/CIRCRESAHA.111.261743
  • 94 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: 2029-2039 . DOI: 10.1101/gad.11.16.2029
  • 95 Zoppi N, Chiarelli N, Cinquina V, Ritelli M, Colombi M. GLUT10 deficiency leads to oxidative stress and non-canonical alphavbeta3 integrin-mediated TGFbeta signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Hum Mol Genet 2015; 24: 6769-6787 . DOI: 10.1093/hmg/ddv382
  • 96 Cheng CH, Kikuchi T, Chen YH, Sabbagha NG, Lee YC, Pan HJ. , et al. Mutations in the SLC2A10 gene cause arterial abnormalities in mice. Cardiovasc Res 2009; 81: 381-388 . DOI: 10.1093/cvr/cvn319
  • 97 Azhar M, Schultz JJ, Grupp I, Dorn 2nd GW, Meneton P, Molin DG. , et al. Transforming growth factor beta in cardiovascular development and function. Cytokine Growth Factor Rev 2003; 14: 391-407 . DOI: 10.1016/S1359-6101(03)00044-3