SMAD3 is associated with Loeys-Dietz syndrome type 3, characterized by cardiac malformation (mitral valve prolapse, aortic insufficiency, left ventricular hypertrophy) and an increased risk of aortic aneurysm and dissection, arterial aneurysm and arterial tortuosity, pectus deformity, and an increased risk of internal organ ruptures [43]. This evidence concerns the gene SMAD3 and aortic valve insufficiency.