Objective: To determine the frequency of distinctive EGFr cysteine altering NOTCH3 mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database.
Methods: ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions. The Dutch CADASIL registry was probed for paucisymptomatic individuals older than 70 years.
Results: We identified 206 EGFr cysteine altering NOTCH3 mutations in ExAC, with a total prevalence of 3.4/1000. More than half of the distinct mutations have been previously reported in CADASIL patients. Despite the clear overlap, the mutation distribution in ExAC differs from that in reported CADASIL patients, as mutations in ExAC are predominantly located outside of EGFr domains 1-6. In an independent Dutch CADASIL cohort, we found that patients with a mutation in EGFr domains 7-34 have a significantly lower MRI lesion load than patients with a mutation in EGFr domains 1-6.
Interpretation: 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.