Interpretation of NOTCH3 mutations in the diagnosis of CADASIL.

[cadasil]

CADASIL is an autosomal dominant inherited disease , characterized by mid-adult onset of cerebrovascular disease and dementia . CADASIL is caused by mutations in the NOTCH 3 gene , which encodes the NOTCH 3 protein . Pathogenic mutations in CADASIL are highly distinctive in the sense that they lead to the loss or gain of a cysteine residue in 1 of the 34 EGFr domains of the NOTCH 3 protein . The majority are missense mutations , but small deletions , insertions and splice-site mutations have been reported , which typically also lead to a numerical cysteine alteration . Whether numerical cysteine-altering mutations are a rule in CADASIL remains subject of debate , as there are reports suggesting pathogenicity of other types of mutations . However , for most of these the association with CADASIL was later revoked or is questionable . Here , we discuss and provide recommendations for the interpretation of NOTCH 3 mutations in the diagnosis of CADASIL .