Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations

Nat Commun. 2023 Nov 17;14(1):7452. doi: 10.1038/s41467-023-43062-z.


To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / genetics
  • Animals
  • Endothelial Cells / pathology
  • GTPase-Activating Proteins / genetics
  • Humans
  • Mice
  • Mutation
  • Mutation, Missense
  • Signal Transduction / genetics
  • Vascular Diseases*
  • Vein of Galen Malformations* / genetics
  • Vein of Galen Malformations* / pathology
  • p120 GTPase Activating Protein / genetics


  • GTPase-Activating Proteins
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • RASA1 protein, human
  • p120 GTPase Activating Protein