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

Daniel Duran, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Xue Zeng, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Sheng Chih Jin, Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
Jungmin Choi, Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
Carol Nelson-Williams, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Bogdan Yatsula, Department of Surgery, Yale School of Medicine, New Haven, CT, USA.
Jonathan Gaillard, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Charuta Gavankar Furey, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Qiongshi Lu, Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
Andrew T. Timberlake, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Weilai Dong, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Michelle A. Sorscher, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Erin Loring, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Jennifer Klein, Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA.
August Allocco, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Ava Hunt, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Sierra Conine, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Jason K. Karimy, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Mark W. Youngblood, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Jinwei Zhang, Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter, UK.
Michael L. DiLuna, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Charles C. Matouk, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Shrikant Mane, Yale Center for Genome Analysis, West Haven, CT, USA.
Irina R. Tikhonova, Yale Center for Genome Analysis, West Haven, CT, USA.
Christopher Castaldi, Yale Center for Genome Analysis, West Haven, CT, USA.
Francesc López-Giráldez, Yale Center for Genome Analysis, West Haven, CT, USA.
James Knight, Yale Center for Genome Analysis, West Haven, CT, USA.
Shozeb Haider, University College London, School of Pharmacy, London, UK.
Mariya Soban, University College London, School of Pharmacy, London, UK; Department of Biochemistry, Aligarh Muslim University, Aligarh, India.
Seth L. Alper, Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.
Masaki Komiyama, Department of Neurointervention, Osaka City General Hospital, Osaka, Japan.
Andrew F. Ducruet, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.Follow

Document Type

Article

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

Medical Subject Headings

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, pathology)

Publication Date

2-6-2019

Publication Title

Neuron

E-ISSN

1097-4199

Volume

101

Issue

3

First Page

429

Last Page

443.e4

PubMed ID

30578106

Digital Object Identifier (DOI)

10.1016/j.neuron.2018.11.041

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