A novel missense variant Cys559Gly in NOTCH3 in CADASIL family and vascular lesions in patients with migraine.

Abstract

Purpose: To report a novel NOTCH3 pathologic variant in a family presenting CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, OMIM #125310).

Case description: Two affected sisters with dementia and ischemic stroke (only the proband) in their medical history, and the pro- band's daughter with migraine without aura underwent clinical and imaging evaluations. Magnetic resonance imaging revealed typical CADASIL lesions in both sisters. Next-generation sequencing and targeted Sanger sequencing were performed to link the phenotype to a variant in the NOTCH3.

Comment: Sequencing data revealed a likely pathogenic variant in the NOTCH3 gene. Using ACMG guidelines, the variant was classified as likely pathogenic. We have described a new likely pathogenic NOTCH3 missense variant c.1675T>G p. (Cys559Gly) and linked it to the CADASIL phenotype, confirming the predictions of genetic analyses. We particularly emphasize co-occurring central vascular lesions in patients with migraine, which may be de facto caused by pathogenic NOTCH3 variants.