A bicuspid aortic valve is a common heart malformation that occurs in 1-2% of the general population. Aneurysms of the ascending aorta are often associated with a bicuspid aortic valve. Patients with a bicuspid aortic valve often develop further complications such as aortic insufficiency, aortic stenosis, and aortic aneurysms and dissections. The genetic etiology of bicuspid aortic valve is heterogeneous. Many patients with a bicuspid aortic valve have a positive family history with autosomal dominant inheritance. Sometimes a bicuspid aortic valve occurs in connection with a syndromic aortic disease such as Loeys-Dietz syndrome or a non-syndromic familial TAAD.
Variants have been identified in the genes TGFBR1, TGFBR2, SMAD3, TGFB2 and TGFB3 as well as FBN1, ACTA2 and MYH11. Variants in the NOTCH1 gene, which codes for a transmembrane receptor of NOTCH signaling transduction, were identified in a maximum of 10% of the investigated families with dominantly inherited bicuspid aortic valve (AOVD1). Variants in SMAD6 (SMA- and MAD-related protein 6), which codes for another molecule within the transforming growth factor ß-signal transmission pathway in the arterial wall, have been described in 1-3% of patients with bicuspid aortic valve and aortic dissections (AOVD2). Variants in ROBO4, which codes for a regulator of endothelial cell migration and angiogenesis (roundabout guidance receptor 4), have so far been identified in 2% of patients with bicuspid aortic valve and ascending aortic aneurysms, some of whom had an atrial septal defect (AOVD3). Variants in GATA5, which codes for a zinc finger transcription factor, were also identified in 1-3% of patients with bicuspid aortic valve.
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