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 This evidence concerns the gene NOTCH3 and stroke disorder.