NOTCH3 and Stroke: Vascular risk factors, particularly smoking and hypertension, have been shown to be associated with an earlier onset of stroke within CADASIL families but only account for a small amount of variability.32 33 Family studies have suggested that as much of 60% of the heritability of WMH lesion volume is accounted for by yet undetermined modifier genetic factors outside the NOTCH3 gene, but the nature of these remains undetermined.34