Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Content Provider	Europe PMC
Author	Mönkäre, Saana Kuuluvainen, Liina Schleutker, Johanna Myllykangas, Liisa Pöyhönen, Minna
Abstract	ObjectivesCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. 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. 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.Materials and MethodsThe 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.ResultsThe 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. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features.ConclusionThis study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene‐panel or exome sequencing is recommended when suspecting CADASIL.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC9825900&blobtype=pdf
Page Count	9
ISSN	00016314
Journal	Acta Neurologica Scandinavica [Acta Neurol Scand]
Volume Number	146
DOI	10.1111/ane.13703
PubMed Central reference number	PMC9825900
Issue Number	5
PubMed reference number	36086804
e-ISSN	16000404
Language	English
Publisher	John Wiley and Sons Inc.
Publisher Date	2022-09-09
Publisher Place	Hoboken
Access Restriction	Open
Rights License	This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.
Subject Keyword	CADASIL Finnish genotype mutation NOTCH3 phenotype
Content Type	Text
Resource Type	Article
Subject	Neurology Neurology (clinical)