Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations

ABSTRACT Deleterious variants in COL4A2 , encoding type IV collagen's alpha‐2 chain, cause heterogeneous cerebrovascular and developmental brain malformations. While many dominant variants are known, biallelic changes are rarely reported. We reported two severe cases: Case #1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption; and Patient #2, a 2‐year‐old girl with neurodevelopmental impairment, cortical malformations (frontal schizencephaly, polymicrogyria), and reduced white matter volume. Exome sequencing identified a homozygous missense COL4A2 variant in case #1 and compound heterozygous loss‐of‐function variants (splicing and truncating) in case #2. All variants were rare and predicted to affect protein stability and function in silico . Our cases reinforce the association between biallelic COL4A2 variants and brain small vessel disease, expanding the recessive COL4A2‐related phenotype to include cortical malformations.