Overall, while further studies are required to address the intriguing possibility that incomplete penetrant NOTCH3 mutations contribute to the pathogenesis not only of CADASIL but also of CCM disease, our finding that the NOTCH3 c.2960G>C variant segregates with CCM disease paves the way forward to exploring its impact on molecular mechanisms involving CCM genes. Here, NOTCH3 is linked to cerebral cavernous malformation.