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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

Idit Tessler 
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
,
Juliette Albuisson 
4   Oncogenetics laboratory, Centre George François Leclerc, Dijon, France
,
Guillaume Goudot
5   Cardiovascular Department, Georges Pompidou European Hospital, Paris, France
,
Shai Carmi 
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.
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Abstract

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.

Keywords

bicuspid aortic valve - genetics - congenital heart disease - thoracic aortic aneurysm - aortic dissection


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. (https://creativecommons.org/licenses/by/4.0/)

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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
    Google Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 3 Tzemos N, Therrien J, Yip J. et al. Outcomes in adults with bicuspid aortic valves. JAMA 2008; 300 (11) 1317-1325
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 5 Ward C. Clinical significance of the bicuspid aortic valve. Heart 2000; 83 (01) 81-85
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 8 Siu SC, Silversides CK. Bicuspid aortic valve disease. J Am Coll Cardiol 2010; 55 (25) 2789-2800
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 11 Garg V, Muth AN, Ransom JF. et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005; 437 (7056): 270-274
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 26 Mortensen KH, Andersen NH, Gravholt CH. Cardiovascular phenotype in Turner syndrome--integrating cardiology, genetics, and endocrinology. Endocr Rev 2012; 33 (05) 677-714
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 29 Escárcega RO, Michelena HI, Bove AA. Bicuspid aortic valve: a neglected feature of Shone's complex?. Pediatr Cardiol 2014; 35 (01) 186-187
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 45 Hales AR, Mahle WT. Echocardiography screening of siblings of children with bicuspid aortic valve. Pediatrics 2014; 133 (05) e1212-e1217
    CrossrefPubMedGoogle Scholar
  • 46 Laforest B, Nemer M. GATA5 interacts with GATA4 and GATA6 in outflow tract development. Dev Biol 2011; 358 (02) 368-378
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar