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

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.