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Common NOTCH3 Variants and Cerebral Small-Vessel Disease
Loes C A Rutten-Jacobs1, Matthew Traylor2, Poneh Adib-Samii2
1From the Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom (L.C.A.R.-J., M.T., S.B., H.S.M.); Stroke and Dementia Research Center, Department of Clinical Neuroscience, St George's University of London, London, United Kingdom (P.A.-S.); Department of Experimental Neurology, KULeuven and Leuven Research Institute for Neuroscience and Disease, University of Leuven, Leuven, Belgium (V.T.); Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium (V.T.); Division of Clinical Neurosciences, Neuroimaging Sciences and Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom (C.S.); Stroke Prevention Research Unit, Nuffield Department of Neuroscience, University of Oxford, Oxford, United Kingdom (P.M.R.); Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milano, Italy (G.B.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany (M.D.); Department of Neurology, Mayo Clinic, Jacksonville, FL (J.M.); Center for Clinical Epidemiology and Biostatistics, Department of Neurology, Hunter Medical Research Institute and School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia (C.L.); Department of Neurology, Center for Human Genetic Research and Massachusetts General Hospital, Boston (N.S.R., J.R.); and Department of Neurology, Leeds General Infirmary, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom (A.H.). LR406@medschl.cam.ac.uk.
Common NOTCH3 gene variants do not appear to increase the risk of sporadic small-vessel disease, including lacunar stroke and white matter hyperintensity. This study found no association between these genetic variations and disease development.
Area of Science:
- Genetics and Neurology
- Cerebrovascular Diseases
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a common monogenic cause of cerebral small-vessel disease, linked to NOTCH3 gene mutations.
- It is hypothesized that common NOTCH3 variants may contribute to sporadic small-vessel disease risk.
Purpose of the Study:
- To investigate the association between common single nucleotide polymorphisms (SNPs) in the NOTCH3 gene and the risk of sporadic small-vessel disease.
- To examine the relationship between common NOTCH3 SNPs and MRI-confirmed white matter hyperintensity volumes.
Main Methods:
- Meta-analysis of genome-wide association study data for 1350 lacunar stroke patients and 7397 controls.
- Analysis of common NOTCH3 SNPs and MRI white matter hyperintensity volumes in 3670 ischemic stroke patients.
- Inclusion of 381 SNPs within the NOTCH3 gene region, with a significance threshold of P<0.0015.
Main Results:
- No significant association was found between common NOTCH3 variants (including rs10404382, rs1043994, rs10423702, and rs1043997) and lacunar stroke.
- No association was observed between common NOTCH3 variants and white matter hyperintensity volume, even when stratified for hypertension.
Conclusions:
- The study does not support a role for common NOTCH3 gene variations in the risk of developing sporadic small-vessel disease.
- Current evidence does not link common NOTCH3 variants to increased susceptibility to lacunar stroke or white matter hyperintensities.
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