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

TL;DR

Biallelic COL4A2 gene variants are linked to severe brain abnormalities, including small vessel disease and cortical malformations, as shown through two clinical cases.

Contribution

The paper expands the known recessive COL4A2-related phenotype to include cortical malformations and provides evidence of protein destabilization.

Findings

Biallelic COL4A2 variants are associated with brain small vessel disease and cortical malformations.

Protein modeling shows that the p.Arg179Cys variant destabilizes COL4A2, supporting its role in disease.

Two cases with rare, loss-of-function COL4A2 variants demonstrate a spectrum of severe brain abnormalities.

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.

Biallelic COL4A2 variants cause a spectrum of brain abnormalities such as brain small vessel disease (BSVD). We describe two cases—one with cerebrovascular disruption and one with cortical malformations—expanding the recessive phenotype. Protein modeling reveals destabilization by p.(Arg179Cys), reinforcing its pathogenic role and highlighting collagen IV's essential function in brain vascular and cortical development.

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