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Study of the NOTCH3 Gene Reveals the First CADASIL Cases in Crete and a Novel Pathogenic Variant

Ioannis Zaganas1,2,3, Ioannis Tsiverdis1, Evgenia Kokosali1

  • 1Neurology/Neurogenetics Laboratory, School of Medicine, University of Crete, Heraklion, Crete, Greece.

Brain and Behavior
|September 26, 2025
PubMed

Insights

This study identified pathogenic NOTCH3 gene variants in individuals with suspected cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Crete, Greece. This marks the first documented cases of CADASIL on the island.

Area of Science:

  • Genetics and Neurology
  • Molecular Medicine

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is linked to NOTCH3 gene variants.
  • No prior reports of CADASIL existed on the Greek island of Crete.

Purpose of the Study:

  • To investigate the presence of pathogenic NOTCH3 variants in individuals with suspected CADASIL on Crete.
  • To document the initial cases of CADASIL in this region.

Main Methods:

  • Medical records of three suspected CADASIL patients from the University Hospital of Heraklion were reviewed.
  • Pathogenic NOTCH3 variants were identified using targeted or whole-exome sequencing (WES).

Main Results:

  • A novel heterozygous NOTCH3 variant (p.Cys206Trp) was identified in a mother and son presenting with stroke, cognitive impairment, and headaches.
  • Brain MRI revealed white matter disease in both patients.
  • A previously described NOTCH3 variant (p.Arg607Cys) was found in a third CADASIL patient.

Conclusions:

  • This study confirms the first cases of CADASIL on Crete.
  • The findings expand the known geographic and genotypic spectrum of pathogenic NOTCH3 variants associated with CADASIL.
Abstract

Keywords:
CADASILNOTCH3dementianeurogeneticsstroke

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