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Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised., Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants., Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches., Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD., Funding: The Wellcome Trust, the MRC., Competing Interests: Declaration of interests Wendy Chung is on the board of directors of Prime Medicine. Stephan Zuchner has received consultancy honoraria from Neurogene, AegleaBioTherapeutics, Applied Therapeutics, and is an unpaid officer of the TGP foundation, all unrelated to the present manuscript. Elisa Fazzi has received honoraria from GW Pharma. Nicola De Stefano has received honoraria from Biogen-Idec, Genzyme, Immunic, Merck, Novartis, Roche, Celgene, and Teva for consulting services, speaking, and travel support. He serves on advisory boards for Merck, Novartis, Biogen-Idec, Immunic, Roche, and Genzyme, and he has received research grant support from the Italian MS Society. Lyn R Griffiths has received grants from the Australian National Health and Medical Research Council, Variant Bio, US Department of Defense and US Migraine Research Foundation as well as honoraria from Teva, Springer Nature, and Association of Migraine Disorders and she is Board of Censors, Diagnostic Genomics Human Genetics Assoc Australia and member of the Human Genetics Australasia Advisory Board. Hugh S Markus has received peer reviewed grants from the Medical Research Council, British Heart Foundation, National Institute of Health Research, and the Alzheimer Society, and is editor in chief of the International Journal of Stroke., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)