Aortic valve disease is a nonsyndromic autosomal dominant disorder characterised by a spectrum of developmental aortic valve anomalies and severe valve calcification. Valve anomalies include bicuspid aortic valve (BAV – aortic valve with 2 rather than 3 leaflets) which is a precursor for aortic valve stenosis or insufficiency and in extreme cases the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. BAV is also associated with increased risk of aortic coarctation (narrowing of thoracic aorta), aortic dissection, aortic aneurysm and infective endocarditis.

NOTCH1 disease-causing variants have been identified in two large families with calcific aortic valve disease usually in the context of a BAV (Garg et al 2005: Nature 437, 270-274).  Subsequent studies have identified NOTCH1 variants in 2/48 (4%) of sporadic cases of BAV (Mohamed et al 2006: Biochem Biophys Res Commun 345(4) 1460-1465).

Screening of the NOTCH1 gene in 91 European American patients with LVOT identified eight different disease-causing variants (9%) across all phenotypes of LVOT (aortic valve stenosis 8/37; BAV 1/5; coarctation of the aorta 2/35; hypoplastic left heart syndrome 3/14) (McBride et al 2008: Hum Mol genet 15(17) 2886-2893.


The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.