COL4A2 – Familial Porencephaly

The COL4A2 gene encodes the type IV collagen α2 chain, a critical component of basement membranes in the cerebral vasculature. Heterozygous variants in COL4A1 are established causes of autosomal dominant porencephaly, and emerging evidence implicates COL4A2 in a similar spectrum of cerebrovascular disease, including familial porencephaly (PMID:22333902).

In two unrelated pedigrees with autosomal dominant inheritance, sequencing identified a heterozygous missense variant c.4165G>C (p.Gly1389Arg) and a heterozygous frameshift c.3206delC leading to premature truncation, each co-segregating with porencephaly, white matter lesions, and small-vessel disease across multiple generations (PMID:22333902). Diagnostic screening of 183 index patients further uncovered three additional COL4A2 mutations in individuals with porencephaly or intracerebral hemorrhage (PMID:25719457).

Collectively, these studies describe five probands with heterozygous COL4A2 variants (PMID:22333902; PMID:25719457). Variants include missense and truncating alleles, consistent with a dominant-negative or haploinsufficiency mechanism.

Functional assays and animal models reinforce the genetic findings. Col4a2 mutant mice develop porencephaly, hydrocephalus, cerebral hemorrhage, and developmental defects mirroring human disease. In patient fibroblasts harboring truncating variants, electron microscopy reveals basement membrane fragmentation and duplication, and biochemical studies demonstrate increased apoptosis without endoplasmic reticulum stress (PMID:22333902).

Phenotypes exhibit reduced penetrance and variable expressivity, encompassing cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm within affected families, suggesting additional modifiers of clinical outcome.

No conflicting evidence has been reported for COL4A2 in familial porencephaly, and COL4A2 sequencing is recommended when COL4A1 testing is negative. Genetic diagnosis of COL4A2 variants informs surveillance for cerebrovascular complications and enables genetic counseling for families.

References

• European journal of human genetics : EJHG | 2012 | COL4A2 mutation associated with familial porencephaly and small-vessel disease. PMID:22333902
• Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature. PMID:25719457

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