Taken together, our data in cultured human cells, mouse models, and samples from humans with SVAS and WBS are the first to our knowledge to implicate a role of the NOTCH signaling pathway and epigenetic remodeling in the pathogenesis of elastin aortopathy and to identify select NOTCH3 pathway members as attractive therapeutic targets for human SVAS and WBS. The gene discussed is ELN; the disease is supravalvular aortic stenosis.