Lekárska genetika a diagnostika 1/2024

Spectrum of pathogenic variants in the NOTCH3 gene in patients with CADASIL syndrome

CADASIL syndrome is an acronym for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. The syndrome is caused by pathogenic variants in the NOTCH3 gene. The most important determinant of disease severity is position of the NOTCH3 pathogenic variant. In comparison with pathogenic variants affecting the epidermal growth factor-like repeat EGFr domains 7 to 34 (exons 6 to 24), pathogenic variants in EGFr domains 1 to 6 (exons 2 to 6) predispose to an earlier onset of stroke, shorter survival, and more pronounced leukodystrophic changes. The diagnosis is confirmed by a molecular-genetic analysis only, which must be preceded by a thorough re-evaluation of clinical symptoms, positive neuroimages and family history. In this study, we describe 18 pathogenic variants in a cohort of 30 probands from unrelated families diagnosed with CADASIL, five of them are novel. Moreover, the wide spectrum of pathogenic variants detected in Slovak patients with CADASIL allows for the investigation of the relationship between the genotype and the phenotype of patients with this serious disease.

Keywords: cerebrovascular diseases, CADASIL syndrome, NOTCH3 gene, molecular-genetic analysis, EGFr domain