Case series of two sisters with intracerebral hemorrhage and COL4A1 gene variant

Introduction Spontaneous intracerebral hemorrhage (sICH) accounts for 10‐20% of all strokes and is a significant cause of disability and mortality. While commonly linked to factors such as hypertension and amyloid angiopathy, sICH can also occur without traditional risk factors, suggesting a genetic basis. Identifying familial patterns of sICH can guide testing and provide valuable insights for affected families. We present two sisters who experienced sICH within the same year, both carrying a COL4A1 gene mutation. Methods Two patients with genetically confirmed COL4A1 gene variant and sICH were reviewed retrospectively including imaging findings. Results A 41‐year‐old woman presented with right‐sided weakness and aphasia, found to have spontaneous left basal ganglia hemorrhage. Digital subtraction angiogram showed concentric vessel narrowing in the middle and anterior cerebral arteries, consistent with medium vessel vasculopathy. Similarly, her 40‐year‐old sister presented with left‐sided weakness and a spontaneous basal ganglia hemorrhage. Despite extensive testing, the cause of hemorrhage remained unclear. Both patients underwent genetic testing which revealed a COL4A1 gene variant. Conclusions The COL4A1 mutation impairs type IV collagen secretion, leading to basement membrane defects that weaken blood vessels and disrupt vascular function. In COL4A1 mutation, sICH predominantly occurs in the basal ganglia and patients may also present with arteriolar tortuosity, migraines, leukoencephalopathy, and dilated perivascular spaces. The condition can exhibit significant phenotypic variability, highlighting the role of strong gene‐environment interactions. These cases emphasize the importance of genetic testing in familial stroke syndromes to inform prevention and optimize management strategies.