Molecular-genetic mechanisms of cerebral arteriovenous malformations: A systematic review of germline, somatic and experimental evidence.
Anton Konovalov, Fyodor Grebenev, Yuri Pilipenko et al.
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In 30 seconds
This systematic review synthesised human genetic, molecular, and experimental evidence on cerebral arteriovenous malformation (AVM) formation, clinical course, and potential therapeutic targets. It included 44 primary studies and 20 reviews or meta-analyses; heterogeneity meant findings were synthesised qualitatively. Inherited AVM syndromes were linked mainly to germline variants in TGF-β/BMP and arteriovenous-specification pathways, while sporadic lesions often showed low-level somatic KRAS, and less often BRAF, mutations. Experimental endothelial activation of KRAS or BRAF produced AVM-like phenotypes dependent on MEK-ERK signalling. The authors conclude that these pathways converge in AVM biology, but diagnostic and therapeutic approaches require prospective evaluation.
Key findings
- The review included 44 primary studies—28 clinico-genetic and 16 experimental—alongside 20 reviews and meta-analyses.
- Inherited syndromes were associated mainly with germline variants in TGF-β/BMP-network genes or arteriovenous-specification regulators; penetrance was incomplete.
- Sporadic resected AVMs often carried low-variant-allele-fraction somatic mutations, mostly KRAS and less often BRAF.
- Endothelial KRAS or BRAF activation reproduced AVM-like phenotypes in vivo, with evidence of MEK-ERK dependence.
Why it matters
The review connects inherited predisposition and somatic endothelial mutations to shared developmental signalling pathways involved in angiogenesis and vessel-wall maturation. This framework may help explain why lesions arise and vary in behaviour, including haemorrhagic risk, and identifies biological targets for further study. It also highlights the need for sensitive detection of low-level mosaicism when investigating AVM genetics.
What to keep in mind
The evidence was substantially heterogeneous in study designs and outcomes, so the review used qualitative synthesis rather than pooled estimates.