Novel loss of function mutation in NOTCH1 in a family with bicuspid aortic valve, ventricular septal defect, thoracic aortic aneurysm, and aortic valve stenosis.

Background: Bicuspid aortic valve is the most common congenital valvular heart defect in the general population. BAV is associated with significant morbidity due to valve failure, formation of thoracic aortic aneurysm, and increased risk of infective endocarditis and aortic dissection. Loss of function mutations in NOTCH1 (OMIM 190198) has previously been associated with congenital heart disease involving the aortic valve, left ventricle outflow tract, and mitral valve that segregates in affected pedigrees as an autosomal dominant trait with variable expressivity. Methods: We performed whole-exome sequencing in four members of a three-generational family (three affected and one unaffected subject) with clinical phenotypes including aortic valve stenosis, thoracic aortic aneurysm, and ventricular septal defect. Results: We identified 16 potentially damaging genetic variants (one stop variant, one splice variant, and 14 missense variants) cosegregating with the phenotype. Of these variants, the nonsense mutation (p.Tyr291*) in NOTCH1 was the most deleterious variant identified and the most likely variant causing the disease. Conclusion: Inactivating NOTCH1 mutations are a rare cause of familial heart disease involving predominantly left ventricular outflow tract lesions and characterized by the heterogeneity of clinical phenotype.