Unraveling The Broad NOTCH3-associated Small Vessel Disease Spectrum: from CADASIL to nonpenetrance

Abstract

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most prevalent hereditary small vessel disease, marked by recurrent subcortical ischemic strokes and progressive vascular cognitive impairment. CADASIL is caused by cysteine-altering variants in the NOTCH3 gene (NOTCH3-cys). The clinical presentation of CADASIL is highly variable, with some individuals experiencing strokes before the age of 30, while others remain stroke-free into their 80s. Recently, a study demonstrated that the position of the NOTCH3-cys variant along the 34 EGFr domains of the NOTCH3 protein is an important intragenic modifier of CADASIL disease severity. The aim of this thesis was to delineate the NOTCH3-associated small vessel disease (NOTCH3-SVD) spectrum and to assess the impact of NOTCH3-cys variant position and cardiovascular risk factors on disease severity. To this end, we utilized genetic, clinical and neuroimaging data from both CADASIL patient cohorts and population biobanks to capture the full disease spectrum. This thesis demonstrates that NOTCH3-cys variants are common in the general population and are associated with a manifold milder SVD phenotype than what is typically seen in CADASIL patients. These milder phenotypes are not only found in the general population, but occasionally occur within established CADASIL pedigrees. Importantly, this work shows that the position of the NOTCH3-cys variant along the 34 EGFr domains is the most significant determinant of disease severity. This thesis refines genotype-based risk stratification by categorizing NOTCH3-cys variants into three distinct NOTCH3-SVD risk categories. Beyond the position of the NOTCH3 variant, additional key modifiers include sex, hypertension, and diabetes. Furthermore, this thesis provides evidence supporting abnormal NOTCH3 aggregation as the primary pathophysiological mechanism in NOTCH3-SVD, as NOTCH3-SVD risk category was found to be strongly associated with vascular NOTCH3 aggregation load, whereas no association was found between NOTCH3-SVD risk category and NOTCH3 signalling properties.​​​​​​​