The transmembrane NOTCH3 receptor, one of the 4 mammalian NOTCH homologs, is primarily expressed by vascular smooth muscle cells, where it plays an important role in cell differentiation and maturation.1 A complete loss of Notch3 causes progressive dilatation and tortuosity of brain vessels in Notch3−/− mice,2 and humans with biallelic NOTCH3 loss-of-function (NOTCH3lof) variants present with a severe, childhood-onset small vessel disease.3-10 Whether monoallelic NOTCH3lof variants also cause a small vessel disease is subject of debate.3,8,10-17. The gene discussed is NOTCH3; the disease is Onset.