The severity of CADASIL varies markedly between patients. We know that vascular risk factors such as smoking make the disease more severe but this only accounts for part of the variability, and much of it remains unexplained. This study from an international European collaboration led from Leiden in The Netherlands examined the site of the CADASIL mutation within the NOTCH3 gene to determine whether it related to disease severity. The age at which CADASIL mutation carriers suffered their first stroke was earlier in those with mutations in the first part of the gene (egf repeats 1-6) compared with mutations in the later part of the gene (egf repeats 7-34). The authors suggested that mutation location may therefore be another factor affecting disease severity. They also looked at databases of people who had had their whole genome sequenced and their early findings suggested that mutations further down the gene may be more common than thought in the general population. This raises the possibility that there may be people in the general population with CADASIL mutations in this part of the gene who have not had symptoms.
Reference: Rutten JW, Van Eijsden BJ, Duering M, Jouvent E, Opherk C, Pantoni L, Federico A, Dichgans M, Markus HS, Chabriat H, Lesnik Oberstein SAJ. The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant. Genet Med. 2019 Mar;21(3):676-682. Click here for PubMed abstract.