COL4A1/COL4A2 as the newly recognized genes associated with cerebral small vessel disease

Abstract

Cerebral small vessel diseases cause lacunar infarcts, cerebral microbleeds, or diffuse white matter diseases. Approximately 5% of them are considered hereditary, including COL4A1/COL4A2–related disorders. COL4A1/COL4A2 encode type IV collagen α1/α2. Heterozygous pathogenic variations in COL4A1/COL4A2, usually missense variants substituting Gly residue at G–X–Y repeat of COL4A1/COL4A2 procollagen peptides, are associated with wide variety of multi–organ phenotypes. As for brain features, they can cause porencephaly, schizencephaly, hydranencephaly, or intraventricular/subependymal hemorrhage as the most severe phenotypes, to adult–onset intracerebral hemorrhage, lacunar stroke, microbleeds, leukoencephalopathy, migraine, or cerebral aneurysm as milder or asymptomatic forms. Other organs possibly affected include eye, kidney, muscle, cardiovascular system, as well as blood (hemolytic anemia). Hereditary angiopathy with nephropathy, aneurysm, and muscle cramp (HANAC syndrome), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), and hereditary multi–infarct dementia of the Swedish type (hMID) are the specific forms of COL4A1–related disorders with respective pathogenic–variant hotspots. The diagnostic yield of COL4A1/COL4A2 in patients with clinically suspected COL4A1/COL4A2–related disorders are around 20%, implying that there might be other genetic cause to explain this disease. Under this hypothesis, we identified COLGALT1 as a novel aberrant gene associated with autosomal recessive cerebral small vessel disease which shares common molecular pathogenesis with COL4A1/COL4A2–related disorders.