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

Silvia Bianchi1, Maria Teresa Dotti, Gian Nicola Gallus

  • 1Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.

Neurobiology of Aging
|April 17, 2013
PubMed

Insights

Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) diagnosis can be challenging. A novel NOTCH3 gene deletion causing aberrant splicing offers new diagnostic insights for genetically undefined cases.

Area of Science:

  • Genetics
  • Neurology
  • Molecular Biology

Background:

  • Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited cerebrovascular disorder.
  • It is characterized by migraine with aura, stroke, cognitive decline, and mood disturbances, typically with adult onset.

Observation:

  • Most CADASIL cases result from missense mutations in the NOTCH3 gene, usually affecting cysteine residues.
  • Previously reported splice site mutations are rare, and some patients lack identified genetic causes.

Findings:

  • A novel intronic deletion (c.341-26_24delAAC) in the NOTCH3 gene was identified in a family with late-onset CADASIL.
  • This deletion induced complete intron 3 retention, leading to an in-frame insertion of 25 amino acids, including a cysteine.

Implications:

  • This is the first report of aberrant NOTCH3 splicing caused by a mutation distant from the canonical splice site.
  • Splicing assays should be considered essential for diagnosing genetically undefined CADASIL cases.

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