Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of familial cerebral small vessel disease in adults and is caused by NOTCH3 variants. Clinical manifestations of CADASIL include recurrent ischemic strokes, dementia, migraine or migraineous headaches, epileptic seizures, and psychiatric disorders. The clinical-radiological phenotype of the disease is also highly variable. In this study, we investigated the variability of clinical, radiological, and genetic data in patients analyzed for NOTCH3 variant in our clinic. Methods: We performed clinical and neuropsychological examination, cerebral magnetic resonance imaging (MRI) and Doppler sonography of cerebral arteries in all patients. Next-generation sequencing test was used for detect variants in NOTCH3 gene from all CADASIL patients. Results: By using the next-generation sequencing method, heterozygous c.380C>T pathogenic variant was detected in the 4th exon of the NOTCH3 gene in 3 patients. This is a previously unreported novel variant and resulted in the replacement of the amino acid Proline at 127th position with Leucine. Discussion and Conclusion: The discovery of this novel pathogenic variant region may contribute to the expansion of the clinical and genetic spectrum of diseases associated with NOTCH3, leading to further research and treatment options for this disease in the future.

1.
Adib-Samii P, Brice G, Martin RJ, Markus HS. Clinical spectrum of CADASIL and the effect of cardiovascular risk factors on phenotype: study in 200 consecutively recruited individuals. Stroke. 2010;41(4):630–4.
2.
Almeida MR, Elias I, Fernandes C, Machado R, Galego O, Santo G. NOTCH3 mutations in a cohort of Portuguese patients within CADASIL spectrum phenotype. Neurogenetics. 2022;23(1):1–9.
3.
Buczek J, Błażejewska-Hyżorek B, Cudna A, Lusawa M, Lewandowska E, Kurkowska-Jastrzębska I, et al. Novel mutation of the NOTCH3 gene in a Polish family with CADASIL. Neurol Neurochir Pol. 2016;50(4):262–4.
4.
Dang J, Lei S, Xia M, Chen J. A novel NOTCH3 mutation and its clinical, neuroimaging and pathological presentation in a Chinese patient with CADASIL: a case report. Medicine. 2022;101(7):e28870.
5.
Dziewulska D, Sulejczak D, Wężyk M. What factors determine phenotype of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)? Considerations in the context of a novel pathogenic R110C mutation in the NOTCH3 gene. Folia Neuropathol. 2017;55(4):295–300.
6.
Ganesan DN, Coste T, Venketasubramanian N. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): still to be considered in the presence of vascular risk factors. Case Rep Neurol. 2020;12(Suppl 1):196−201.
7.
Grami N, Chong M, Lali R, Mohammadi-Shemirani P, Henshall DE, Rannikmäe K, et al. Global assessment of mendelian stroke genetic prevalence in 101,635 individuals from 7 ethnic groups. Stroke. 2020;51(4):1290–3.
8.
Hung LY, Ling TK, Lau NKC, Cheung WL, Chong YK, Sheng B, et al. Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: a novel mutation within the intracellular domain of NOTCH3. J Clin Neurosci. 2018;56:95–100.
9.
Ince B, Benbir G, Siva A, Saip S, Utku U, Celik Y, et al. Clinical and radiological features in CADASIL and NOTCH3-negative patients: a multicenter study from Turkey. Eur Neurol. 2014;72(3-4):125–31.
10.
Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, Vayssière C, et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997;350(9090):1511–5.
11.
Kim Y, Bae JS, Lee JY, Song HK, Lee JH, Lee, M, et al. Genotype and phenotype differences in CADASIL from an asian perspective. Int J Mol Sci. 2022;23(19):11506.
12.
Kim Y, Lee SH. Novel characteristics of race-specific genetic functions in Korean CADASIL. Medicina. 2019;55(9):521.
13.
Li CS, Wang TW, Wang J, Li SH, Li N, Wang XS, et al. Phenotypic characterization of CADASIL patients with the Arg332Cys mutation in the NOTCH3. Ann Transl Med. 2020;8(1):10.
14.
Manini A, Pantoni L. CADASIL from bench to bedside: disease models and novel therapeutic approaches. Mol Neurobiol. 2021;58(6):2558–73.
15.
Mosca L, Marazzi R, Ciccone A, Santilli I, Bersano A, Sansone V, et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J Neurol Sci. 2011;307(1-2):144–8.
16.
Mönkäre S, Kuuluvainen L, Schleutker J, Myllykangas L, Pöyhönen M. Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Acta Neurol Scand. 2022;146(5):643–51.
17.
Okada T, Washida K, Irie K, Saito S, Noguchi M, Tomita A, et al. Prevalence and atypical clinical characteristics of NOTCH3 mutations among patients admitted for acute lacunar infarctions. Front Aging Neurosci. 2020;12(12):130.
18.
Rüstemoğlu BS, Samanci B, Tepgeç F, Kürtüncü M, Altunoglu M, Gündüz T, et al. Clinical and molecular genetic findings of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy. Turk J Neurol. 2021;27(3):240–7.
19.
Tikka S, Mykkänen K, Ruchoux MM, Bergholm R, Junna M, Pöyhönen M, et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain. 2009;132(Pt 4):933–9.
20.
Xiromerisiou G, Marogianni C, Dadouli K, Zompola C, Georgouli D, Provatas A, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: genotype-phenotype correlations of all published cases. Neurol Genet. 2020;6(3):e434.
You do not currently have access to this content.