Disruption of the vascular ECM has been hypothesised to be a key component in pathogenesis of cerebral small vessel disease, particularly in monogenic forms, and several of the genes implicated in this study (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1) have key roles in the ECM.70 This evidence concerns the gene HTRA1 and cerebral small vessel disease.