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Monoallelic cysteine-altering NOTCH3 (NOTCH3cys) variants cause CADASIL, a well-characterized adult-onset small vessel disease, whereas biallelic NOTCH3 loss-of-function (NOTCH3lof) variants lead to a rare childhood-onset small vessel disease. This study clarifies that monoallelic NOTCH3lof variants also contribute to a distinct small vessel disease phenotype characterized by increased white matter hyperintensities but without a substantially increased stroke risk compared to controls. Cardiovascular risk factors and aging worsen clinical manifestations. Notably, vessel pathology in NOTCH3lof differs from CADASIL, especially in collagen deposition patterns.