Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL

The frequency of EGFr cysteine altering NOTCH3 mutations is 100-fold higher than expected based on estimates of CADASIL prevalence. This challenges the current CADASIL disease paradigm, and suggests that certain mutations may more frequently cause a much milder phenotype, which may even go clinically unrecognized. Our data suggest that individuals with a mutation located in EGFr domains 1-6 are predisposed to the more severe "classical" CADASIL phenotype, whereas individuals with a mutation outside of EGFr domains 1-6 can remain paucisymptomatic well into their eighth decade.