CC BY 4.0 · Aorta (Stamford) 2021; 09(04): 139-146
DOI: 10.1055/s-0041-1730294
State-of-the-Art Review

Bicuspid Aortic Valve: Genetic and Clinical Insights

1   Department of Cardiology, Hadassah Medical Center, Jerusalem, Israel
2   Faculty of Medicine, The Hebrew University, Jerusalem, Israel
3   Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
4   Oncogenetics laboratory, Centre George François Leclerc, Dijon, France
Guillaume Goudot
5   Cardiovascular Department, Georges Pompidou European Hospital, Paris, France
2   Faculty of Medicine, The Hebrew University, Jerusalem, Israel
3   Braun School of Public Health and Community Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
Shoshana Shpitzen
1   Department of Cardiology, Hadassah Medical Center, Jerusalem, Israel
Emmanuel Messas
5   Cardiovascular Department, Georges Pompidou European Hospital, Paris, France
Dan Gilon
1   Department of Cardiology, Hadassah Medical Center, Jerusalem, Israel
2   Faculty of Medicine, The Hebrew University, Jerusalem, Israel
Ronen Durst
1   Department of Cardiology, Hadassah Medical Center, Jerusalem, Israel
2   Faculty of Medicine, The Hebrew University, Jerusalem, Israel
› Author Affiliations
Funding The study was supported by the Hadassah-Franch Association and the Center for Interdisciplinary Data Science Research of the Hebrew University.


Bicuspid aortic valve (BAV) is the most common valvular congenital heart disease, with a prevalence of 0.5 to 2% in the general population. Patients with BAV are at risk for developing cardiovascular complications, some of which are life-threatening. BAV has a wide spectrum of clinical presentations, ranging from silent malformation to severe and even fatal cardiac events. Despite the significant burden on both the patients and the health systems, data are limited regarding pathophysiology, risk factors, and genetics. Family studies indicate that BAV is highly heritable, with autosomal dominant inheritance, incomplete penetrance, variable expressivity, and male predominance. Owing to its complex genetic model, including high genetic heterogenicity, only a few genes were identified in association with BAV, while the majority of BAV genetics remains obscure. Here, we review the different forms of BAV and the current data regarding its genetics. Given the clear heritably of BAV with the potential high impact on clinical outcome, the clinical value and cost effectiveness of cascade screening are discussed.

Publication History

Received: 22 April 2020

Accepted: 25 February 2021

Article published online:
03 December 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (

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  • References

  • 1 Braverman AC. The bicuspid aortic valve and associated aortic disease. In: Otto CM, Bonow RO. eds. Valvular Heart Disease. 4th ed.. Philadelphia, PA: Saunders/Elsevier; 2013: 179-198
  • 2 Roberts WC, Ko JM. Frequency by decades of unicuspid, bicuspid, and tricuspid aortic valves in adults having isolated aortic valve replacement for aortic stenosis, with or without associated aortic regurgitation. Circulation 2005; 111 (07) 920-925
  • 3 Tzemos N, Therrien J, Yip J. et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008; 300 (11) 1317-1325
  • 4 Michelena HI, Khanna AD, Mahoney D. et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA 2011; 306 (10) 1104-1112
  • 5 Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000; 83 (01) 81-85
  • 6 Loscalzo ML, Goh DLM, Loeys B, Kent KC, Spevak PJDH, Dietz HC. Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance. Am J Med Genet A 2007; 143A (17) 1960-1967
  • 7 Cripe L, Andelfinger G, Martin LJ, Shooner K, Benson DW. Bicuspid aortic valve is heritable. J Am Coll Cardiol 2004; 44 (01) 138-143
  • 8 Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol 2010; 55 (25) 2789-2800
  • 9 Martin PS, Kloesel B, Norris RA, Lindsay M, Milan D, Body SC. Embryonic development of the bicuspid aortic valve. J Cardiovasc Dev Dis 2015; 2 (04) 248-272
  • 10 Marian AJ. Causality in genetics: the gradient of genetic effects and back to Koch's postulates of causality. Circ Res 2014; 114 (02) e18-e21
  • 11 Garg V, Muth AN, Ransom JF. et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005; 437 (7056): 270-274
  • 12 Preuss C, Capredon M, Wünnemann F. et al; MIBAVA Leducq consortium. Family based whole exome sequencing reveals the multifaceted role of notch signaling in congenital heart disease. PLoS Genet 2016; 12 (10) e1006335
  • 13 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
  • 14 Luyckx I, Kumar AA, Reyniers E. et al; MIBAVA Leducq Consortium. Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene. Eur J Hum Genet 2019; 27 (07) 1033-1043
  • 15 de Pater E, Ciampricotti M, Priller F. et al. Bmp signaling exerts opposite effects on cardiac differentiation. Circ Res 2012; 110 (04) 578-587
  • 16 van de Laar IMBH, van der Linde D, Oei EHG. et al. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012; 49 (01) 47-57
  • 17 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
  • 18 Laforest B, Andelfinger G, Nemer M. Loss of Gata5 in mice leads to bicuspid aortic valve. J Clin Invest 2011; 121 (07) 2876-2887
  • 19 Yang B, Zhou W, Jiao J. et al. Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve. Nat Commun 2017; 8: 15481
  • 20 Padang R, Bagnall RD, Richmond DR, Bannon PG, Semsarian C. Rare non-synonymous variations in the transcriptional activation domains of GATA5 in bicuspid aortic valve disease. J Mol Cell Cardiol 2012; 53 (02) 277-281
  • 21 Xu Y-J, Di R-M, Qiao Q. et al. GATA6 loss-of-function mutation contributes to congenital bicuspid aortic valve. Gene 2018; 663: 115-120
  • 22 Gharibeh L, Komati H, Bossé Y. et al; Bicuspid Aortic Valve Consortium. GATA6 regulates aortic valve remodeling, and its haploinsufficiency leads to right-left type bicuspid aortic valve. Circulation 2018; 138 (10) 1025-1038
  • 23 Qu X-K, Qiu X-B, Yuan F. et al. A novel NKX2.5 loss-of-function mutation associated with congenital bicuspid aortic valve. Am J Cardiol 2014; 114 (12) 1891-1895
  • 24 Gould RA, Aziz H, Woods CE. et al; Baylor-Hopkins Center for Mendelian Genomics, MIBAVA Leducq Consortium. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nat Genet 2019; 51 (01) 42-50
  • 25 Martin LJ, Ramachandran V, Cripe LH. et al. Evidence in favor of linkage to human chromosomal regions 18q, 5q and 13q for bicuspid aortic valve and associated cardiovascular malformations. Hum Genet 2007; 121 (02) 275-284
  • 26 Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in Turner syndrome--integrating cardiology, genetics, and endocrinology. Endocr Rev 2012; 33 (05) 677-714
  • 27 Nistri S, Porciani MC, Attanasio M, Abbate R, Gensini GF, Pepe G. Association of Marfan syndrome and bicuspid aortic valve: frequency and outcome. Int J Cardiol 2012; 155 (02) 324-325
  • 28 Milleron O, Ropers J, Arnoult F. et al. Clinical significance of aortic root modification associated with bicuspid aortic valve in Marfan syndrome. Circ Cardiovasc Imaging 2019; 12 (03) e008129
  • 29 Escárcega RO, Michelena HI, Bove AA. Bicuspid aortic valve: a neglected feature of Shone's complex?. Pediatr Cardiol 2014; 35 (01) 186-187
  • 30 Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George Jr. ALJ, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet 2002; 71 (03) 663-668
  • 31 Prakash SK, Bossé Y, Muehlschlegel JD. et al; BAVCon Investigators. A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: insights from the International BAVCon (Bicuspid Aortic Valve Consortium). J Am Coll Cardiol 2014; 64 (08) 832-839
  • 32 Lee TC, Zhao YD, Courtman DW, Stewart DJ. Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. Circulation 2000; 101 (20) 2345-2348
  • 33 Mommersteeg MTM, Yeh ML, Parnavelas JG, Andrews WD. Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves. Cardiovasc Res 2015; 106 (01) 55-66
  • 34 Aicher D, Urbich C, Zeiher A, Dimmeler S, Schäfers H-J. Endothelial nitric oxide synthase in bicuspid aortic valve disease. Ann Thorac Surg 2007; 83 (04) 1290-1294
  • 35 Biben C, Weber R, Kesteven S. et al. Cardiac septal and valvular dysmorphogenesis in mice heterozygous for mutations in the homeobox gene Nkx2-5. Circ Res 2000; 87 (10) 888-895
  • 36 Thomas PS, Sridurongrit S, Ruiz-Lozano P, Kaartinen V. Deficient signaling via Alk2 (Acvr1) leads to bicuspid aortic valve development. PLoS One 2012; 7 (04) e35539
  • 37 Schaefer BM, Lewin MB, Stout KK. et al. The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape. Heart 2008; 94 (12) 1634-1638
  • 38 Fernández B, Durán AC, Fernández-Gallego T. et al. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities. J Am Coll Cardiol 2009; 54 (24) 2312-2318
  • 39 Robledo-Carmona J, Rodríguez-Bailón I, Carrasco-Chinchilla F. et al. Hereditary patterns of bicuspid aortic valve in a hundred families. Int J Cardiol 2013; 168 (04) 3443-3449
  • 40 Tessler I, Goudot G, Albuisson J. et al. Is bicuspid aortic valve, morphology genetically determined? A family-based study. Am J Cardiol 2021; (e-pub ahead of print) DOI: 10.1016/j.amjcard.2021.09.051.
  • 41 Nishimura RA, Otto CM, Bonow RO. et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: A report of the American college of cardiology/American heart association task force on practice guidelines. Circulation 2014; 129 (23) 2440-2492
  • 42 Baumgartner H, Falk V, Bax JJ. et al; ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017; 38 (36) 2739-2791
  • 43 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
  • 44 Tessler I, Leshno M, Shmueli A, Shpitzen S, Durst R, Gilon D. Cost-effectiveness analysis of screening for first-degree relatives of patients with bicuspid aortic valve. Eur Heart J Qual Care Clin Outcomes 2021; 7 (05) 447-457
  • 45 Hales AR, Mahle WT. Echocardiography screening of siblings of children with bicuspid aortic valve. Pediatrics 2014; 133 (05) e1212-e1217
  • 46 Laforest B, Nemer M. GATA5 interacts with GATA4 and GATA6 in outflow tract development. Dev Biol 2011; 358 (02) 368-378
  • 47 Quintero-Rivera F, Xi QJ, Keppler-Noreuil KM. et al. MATR3 disruption in human and mouse associated with bicuspid aortic valve, aortic coarctation and patent ductus arteriosus. Hum Mol Genet 2015; 24 (08) 2375-2389
  • 48 Guo B, McMillan BJ, Blacklow SC. Structure and function of the Mind bomb E3 ligase in the context of Notch signal transduction. Curr Opin Struct Biol 2016; 41: 38-45