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Neurobiol Aging. 2013 Sep;34(9):2234.e9-12. doi: 10.1016/j.neurobiolaging.2013.03.005. Epub 2013 Apr 12.

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

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Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.


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 (30s-60s) adult onset. Genetic testing is the gold standard for the diagnosis. CADASIL is caused mostly by missense mutations in the NOTCH3 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 NOTCH3 gene (c.341-26_24delAAC). 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 NOTCH3 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.

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