Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun 24;108(14):1114-1120.
doi: 10.1136/heartjnl-2021-320428.

Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

Radoslaw Marek Debiec  1   2 , Stephen E Hamby  3 , Peter D Jones  3 , Kassem Safwan  4 , Michael Sosin  5 , Simon Lee Hetherington  6 , David Sprigings  7 , David Sharman  7 , Kelvin Lee  8 , Pegah Salahshouri  9 , Nigel Wheeldon  10 , Andrew Chukwuemeka  11 , Vasiliki Boutziouka  3 , Mohamed Elamin  12 , Sue Coolman  3 , Manish Asiani  3 , Shireen Kharodia  3 , Gregory J Skinner  2 , Nilesh J Samani  3 , Tom R Webb  3 , Aidan P Bolger  3   2
Affiliations

Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

Radoslaw Marek Debiec et al. Heart. .

Abstract

Introduction: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated.

Aim: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations.

Methods: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease.

Results: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees.

Conclusions: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.

Keywords: bicuspid aortic valve; genetics.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Family trees and phenotypic information of eight pedigrees with familial form of BAV disease. AD, aortic dissection; AS, aortic valve stenosis; BAV, bicuspid aortic valve (R+L, right-coronary and left-coronary cusp fusion; R+N, right-coronary and non-coronary leaflet fusion; U, unknown leaflet fusion pattern); CoA, coarctation of aorta; TAA, thoracic aortic aneurysm; VSD, ventricular septal defect.
Figure 2
Figure 2
Study design and key findings. BAV, bicuspid aortic valve; BRAVE, Bicuspid aoRtic vAlVe gEnetic research; CoA, coarctation of aorta; VSD, ventricular septal defect.
See this image and copyright information in PMC

Comment in

References

    1. Hoffman JIE, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002;39:1890–900. 10.1016/S0735-1097(02)01886-7 - DOI - PubMed
    1. Michelena HI, Desjardins VA, Avierinos J-F, et al. . Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation 2008;117:2776–84. 10.1161/CIRCULATIONAHA.107.740878 - DOI - PMC - PubMed
    1. Cripe L, Andelfinger G, Martin LJ, et al. . Bicuspid aortic valve is heritable. J Am Coll Cardiol 2004;44:138–43. 10.1016/j.jacc.2004.03.050 - DOI - PubMed
    1. Galian-Gay L, Carro Hevia A, Teixido-Turà G, et al. . Familial clustering of bicuspid aortic valve and its relationship with aortic dilation in first-degree relatives. Heart 2019;105:603–8. 10.1136/heartjnl-2018-313802 - DOI - PubMed
    1. Garg V, Muth AN, Ransom JF, et al. . Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270–4. 10.1038/nature03940 - DOI - PubMed

Publication types