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

Abstract

Background

NOTCH3 gene variants are associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In this study we aimed to examine the presence of pathogenic NOTCH3 variants in individuals with suspected CADASIL on the Greek island of Crete. This represents the first report of CADASIL patients in Crete.

Methods

We reviewed the medical records of the University Hospital of Heraklion and identified three patients with the clinical diagnosis of CADASIL. In these patients pathogenic NOTCH3 variants were identified through targeted or whole-exome sequencing (WES).

Results

A novel heterozygous variant in exon 4 of the NOTCH3 gene (p.Cys206Trp; NM_000435.3:c.618C>G) was found in a 67-year-old woman who suffered from recurrent ischemic strokes, cognitive impairment, depression, and headache, as well as her son, who presented with headache, anxiety disorder, and insomnia. Brain MRI for both patients revealed white matter disease, including the anterior temporal lobes. The characteristics of this variant (a Cys-related variant in the epidermal growth factor repeats area) support its pathogenicity. We also identified a 72-year-old patient affected by CADASIL and carrying a previously described p.Arg607Cys (NM_000435.3:c.1819C>T) NOTCH3 variant.

Conclusions

This report extends the geographic and genotypic spectrum of pathogenic NOTCH3 variants and documents the first CADASIL cases on the island of Crete, Greece.