Thoracic aortic aneurysms (TAA) consist of abnormal dilation or the widening of a portion of the ascending aorta, due to weakness or destructuring of the walls of the vessel and are potentially lethal. The congenital bicuspid aortic valve (BAV) is considered a risk factor for the development of TAA because asymmetric blood flow through the bicuspid aortic valve detrimentally influences the wall of the ascending aorta.NOTCH1mutations have been associated with non-syndromic TAAs as a consequence of BAV, but little is known regarding its haploinsufficiency and its relationship with connective tissue abnormalities. We report two cases in which there is clear evidence that alterations in theNOTCH1gene are the cause of TAA in the absence of BAV. On the one hand, we describe a 117 Kb deletion that includes a large part of theNOTCH1gene and no other coding genes, suggesting that haploinsufficiency can be considered a pathogenic mechanism for this gene associated with TAA. In addition, we describe two brothers who carry two variants, one in theNOTCH1gene and another in theMIB1gene, corroborating the involvement of different genes of the Notch pathway in aortic pathology.