NOTCH3 and HTRA1 mutations seem to cause ECM disruption by converging pathways, while COL4A1/2 mutations result in disruption of the collagen-IV matrix essential for ECM integrity.92 Increasing evidence suggests monogenic and sporadic SVD share disease mechanisms; common variants in both HTRA1 and COL4A1/2 have been associated with both sporadic lacunar stroke and WMH.13,15. This evidence concerns the gene COL4A1 and snowflake vitreoretinal degeneration.