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

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• COL4A2 gene encodes the alpha-2 chain of type IV collagen, crucial for cerebrovascular and brain development.
• Dominant COL4A2 variants are associated with brain malformations, but biallelic (recessive) variants are infrequently documented.
• Previous research highlights COL4A2's role in cerebrovascular integrity and neuronal development.

Purpose of the Study:

• To investigate the phenotypic spectrum of recessive COL4A2 variants.
• To characterize severe cerebrovascular and developmental brain malformations associated with biallelic COL4A2 mutations.
• To expand the understanding of COL4A2-related disorders.

Main Methods:

• Whole exome sequencing was performed on affected individuals and family members.
• In silico analysis was used to predict the functional impact of identified COL4A2 variants.
• Clinical data from two severe cases with distinct brain malformations were analyzed.

Main Results:

• A homozygous missense COL4A2 variant was identified in a fetus with severe brain abnormalities including calcifications and hemorrhages.
• Compound heterozygous loss-of-function COL4A2 variants were found in a child with cortical malformations and reduced white matter volume.
• All identified variants were rare and predicted to be deleterious to COL4A2 protein function and stability.

Conclusions:

• Biallelic COL4A2 variants are associated with severe cerebrovascular and developmental brain diseases.
• The phenotype of recessive COL4A2 mutations extends to include cortical malformations such as schizencephaly and polymicrogyria.
• These findings broaden the spectrum of COL4A2-related disorders and emphasize the importance of considering recessive inheritance patterns.