PhD Scientific Days 2022

Neurosciences I. (Poster discussion will take place in the Aula during the Coffee Break)

Genetic epidemiology analysis of NOTCH3 gene mutations in Hungary

Text of the abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary, small vessel disease causing stroke. The disease is frequently associated with migraine, progressive cognitive decline, and psychiatric disturbances. The worldwide prevalence of CADASIL has been estimated at approximately 2-4:100,000.
Aims:In this study, we investigated the frequency of pathogenic variants from the coding region of the NOTCH3 gene in Hungarian CADASIL patients and the associations of the pathogenic alterations with the detailed clinical phenotype and MRI findings.

Methods: Total coding region of the NOTCH3 gene was analysed with Sanger or NGS sequencing in 650 patients (359 male, 291 female; mean age 45.27±15.95 years) with small vessel disease features. Brain MRI showed multiple cerebral infarcts and white matter lesions in all cohorts and no risk factors for cerebrovascular abnormalities.

Results: In our study, in 52 of 650 patients (8%), 19 missense substitutions were identified. Among them, 4 were novel, likely pathogenic alterations (p. C222S, G420C, R133C, R207C), these variants were not present in controls and were predicted as disease causing by in silico analysis. The R90C mutation in exon 3 of NOTCH3 gene was the most frequently observed variant (68%), followed by R153C in exon 4 (21%). The clinical symptoms of the positive cases were divided into 4 groups. The most common symptom was TIA/stroke (69%), followed by migraine (52%) in approximately quarter of cases with aura, psychiatric disturbances (29%) and cognitive decline (25%). In retrospectively study of clinical data, we found a higher number of patients having leukoencephalopathy (86%) on brain MRI scans and the white matter lesions appear earlier on cranial MRI than symptoms of CADASIL.

Conclusion: The frequency of the variants was 8% In the Hungarian cohort the most common alteration was the R90C with 2.5% mutation frequency. These results broaden the genetic background and clinical spectrum of CADASIL in the Hungarian population. Based on our experiments, we recommend the genetic analysis of the NOTCH3 gene in patients with stroke / TIA, migraine and leukoencephalopathy.

Funding:The study was supported by the Semmelweis University StartUp, NKFIH_ 132812 and UNKP-21-5 grants.