![]() ![]() The aim of this study was to study the spectrum of disease-causing NOTCH3 variants in the Finnish population and to assess genotype–phenotype correlations of the variants. 10 Until now, the spectrum and prevalence of other NOTCH3 variants in Finnish CADASIL patients has been unknown. 8, 9 In Finland, most of the CADASIL patients carry the variant c.397C>T,(p.Arg133Cys), due to the founder effect. 1 However, other types of variants, such as deletions, duplications, and splice-site variants, including cysteine-sparing variants have also been described in CADASIL families. Typically, the disease-causing variants are missense variants causing an uneven number of cysteine residues within one of the 34 EGFRs of the Notch3 extracellular domain. 2, 7 The majority of disease-causing variants in NOTCH3 occur in exons 2–24. The Notch3 protein is comprised of an extracellular domain with 34 epidermal growth factor repeats (EGFR), three Notch/Lin12 repeats (LNR), a transmembrane domain and an intracellular domain. The NOTCH3 gene consists of 33 exons and encodes a transmembrane receptor Notch3. 3 Clinical presentation of CADASIL is highly variable even between patients with the same pathogenic variant and within families. 1, 2 CADASIL typically presents in young or mid-adulthood and the characteristic clinical features include migraine with aura, recurrent cerebral ischemic events, cognitive impairment and dementia, and mood disturbances. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.Ĭerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene located in the chromosome region 19p13. This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features. The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. Submitted comments are subject to editing and editor review prior to posting.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene.Read any comments already posted on the article prior to submission. Submit only on articles published within 6 months of issue date.(Exception: original author replies can include all original authors of the article) Submissions should not have more than 5 authors.Reference 1 must be the article on which you are commenting. Submissions must be You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid If you are responding to a comment that was written about an article you originally authored: Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment. You must have updated your disclosures within six months: If you are uploading a letter concerning an article: ![]()
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