Distinct Small Vessel Disease Phenotype Linked to Monoallelic NOTCH3 Loss-of-Function Variants: Differentiation from CADASIL and Clinical Implications

Highlight

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.

Study Background and Disease Burden