title: NOTCH3 variants in patients with subcortical vascular cognitive impairment: a comparison with typical CADASIL patients.
abstract: Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is thought to be a common form of hereditary subcortical vascular cognitive impairment (SVCI), there is little data on the frequency of NOTCH3 variants in SVCI patients. We prospectively screened for NOTCH3 variants in consecutive SVCI patients who underwent brain magnetic resonance imaging and amyloid positron emission tomography as well as sequence analysis for mutational hotspots in the NOTCH3 gene. Among 117 patients with SVCI, 16 patients had either known mutations or variants of unknown significance in the NOTCH3 gene. There were no differences in clinical and neuroimaging features between SVCI patients with and without NOTCH3 variants, only except for a higher number of deep microbleeds in SVCI patients with NOTCH3 variants. Our findings suggest that there is a phenotypic entity of NOTCH3 variant that is similar to that of sporadic SVCI but not of typical CADASIL. Notably, 2 SVCI patients with NOTCH3 mutations showed significant amyloid burden, which challenges the prevailing concept that CADASIL represents the genetic model of pure small vessel disease.
authors.affiliation: Department of Neurology, Inha University School of Medicine, Incheon, Korea.
authors.forename: Cindy W
authors.initials: CW
authors.lastname: Yoon
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Kim
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Neuroscience Center, Samsung Medical Center, Seoul, Korea; Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Korea; Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA; Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Electronic address: sangwonseo@empal.com.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Seo
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: changski@skku.edu.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Neurology, Inha University School of Medicine, Incheon, Korea.
authors.forename: Seong Hye
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Duk L
authors.initials: DL
authors.lastname: Na
mesh_terms: D000368:Aged; D058227:Amyloidogenic Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D046589:CADASIL / Q000235:genetics*; D015140:Dementia, Vascular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D059906:Neuroimaging; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*
chemical_list: D058227:Amyloidogenic Proteins; C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: CADASIL; NOTCH3; Subcortical vascular cognitive impairment (SVCI)