First deep intronic mutation in the NOTCH3 gene in a family with late-onset CADASIL.

[cadasil]

CADASIL is the most prominent inherited form of vascular dementia . The main clinical features include migraine with aura , stroke , mood disturbances , and cognitive decline , with a mid-life (30 s-60 s ) adult onset . Genetic testing is the gold standard for the diagnosis . CADASIL is caused mostly by missense mutations in the NOTCH 3 gene , invariably involving a cysteine residue . Only a couple of splice site mutations have been reported . In a few pathologically defined patients , genetic mutations remain unidentified . We report a family with late-onset CADASIL phenotype carrying a novel intronic deletion in the NOTCH 3 gene (c .341 -26 _24 delAAC ). Transcript analysis revealed a splicing alteration , with the complete intron 3 retention . The insertion was in -frame and encoded an extra 25 amino acids , including 1 cysteine . This is the first report of an aberrant splicing event of the NOTCH 3 gene associated with a mutation far away from the canonical splice site . Our finding suggests that the assays used to evaluate splicing should be mandatory in the diagnostic setting of genetically undefined CADASIL cases .