Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation

Neuron. 2019 Feb 6;101(3):429-443.e4. doi: 10.1016/j.neuron.2018.11.041. Epub 2018 Dec 18.

Abstract

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.

Keywords: EPHB4; Vein of Galen malformation; arterio-venous malformation; chromatin modifier; de novo mutations; ephrin signaling; pediatric neurosurgery; whole exome sequencing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromatin Assembly and Disassembly / genetics*
  • Ephrins / metabolism
  • Female
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Metalloendopeptidases / genetics
  • Mutation*
  • Pedigree
  • Penetrance
  • Receptor, EphB4 / genetics
  • Signal Transduction
  • Vein of Galen Malformations / genetics*
  • Vein of Galen Malformations / pathology

Substances

  • Ephrins
  • Membrane Glycoproteins
  • Receptor, EphB4
  • KEL protein, human
  • Metalloendopeptidases