NOTCH3 mutations in a cohort of Portuguese patients within CADASIL spectrum phenotype

Area of Science:

• Neurology
• Genetics
• Vascular Medicine

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent inherited cerebral small vessel disease.
• NOTCH3 gene mutations, primarily cysteine-altering variants, are the known cause of CADASIL.
• Geographic variations exist in the distribution of NOTCH3 mutations.

Purpose of the Study:

• To perform mutation analysis of the NOTCH3 gene in Portuguese families with suspected CADASIL.
• To identify novel NOTCH3 variants and characterize their distribution within the Portuguese population.
• To provide evidence for targeted genetic testing and improved clinical management of CADASIL.

Main Methods:

• Genetic analysis of the NOTCH3 gene in 24 Portuguese families with suspected CADASIL.
• Identification and characterization of heterozygous variants, including cysteine-altering, cysteine-sparing, and nonsense variants.
• Analysis of variant distribution across specific exons of the NOTCH3 gene.

Main Results:

• Fifteen distinct heterozygous NOTCH3 variants were identified in the study cohort.
• Eight pathogenic cysteine-altering variants, six cysteine-sparing variants, and one nonsense variant were detected.
• The majority of identified variants were located in exons 4, 8, and 11 of the NOTCH3 gene.

Conclusions:

• The study identified specific NOTCH3 exons (4, 8, 11) as primary targets for genetic testing in the Portuguese population.
• The findings expand the known spectrum of CADASIL-associated mutations and phenotypes.
• This research offers valuable insights for genetic counseling and clinical management strategies for CADASIL.