Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia

Area of Science:

• Neurology
• Genetics
• Vascular Biology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a common hereditary vascular disorder leading to strokes.
• Early CADASIL diagnosis is challenging due to variable clinical presentations and incomplete symptom profiles.
• NOTCH3 gene pathogenic variants and specific brain MRI findings are crucial for CADASIL diagnosis.

Purpose of the Study:

• To report the first comprehensive findings on CADASIL patients from Slovakia.
• To identify and characterize pathogenic NOTCH3 gene variants in a Slovak cohort.
• To correlate identified genotypes with clinical phenotypes and propose revised diagnostic criteria.

Main Methods:

• Genetic analysis of the NOTCH3 gene in patients with clinical suspicion of CADASIL.
• Identification and sequencing of pathogenic variants.
• Phenotype-genotype correlation analysis.
• Review of current diagnostic criteria for NOTCH3 gene analysis.

Main Results:

• Identified 23 distinct pathogenic NOTCH3 variants in 35 unrelated Slovak families.
• Confirmed a genetic diagnosis in 10.2% of patients with suspected CADASIL.
• Reported novel NOTCH3 variants including p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys), p.(Asp1720His), and p.(Asp1893Thrfs*13).
• Found the most frequent variant location in exon 4 and the most common single variant as p.Arg1076Cys in exon 20.

Conclusions:

• The study provides valuable insights into the genetic landscape of CADASIL in Slovakia.
• The findings support the need for re-evaluation of current criteria for NOTCH3 genetic testing.
• Less stringent criteria for genetic testing are recommended to facilitate earlier and broader CADASIL diagnosis.