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

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

Author information

1
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
2
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
3
Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
4
Department of Surgery, Yale School of Medicine, New Haven, CT, USA.
5
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
6
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA.
8
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
9
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Hatherly Laboratory, Exeter, UK.
10
Yale Center for Genome Analysis, West Haven, CT, USA.
11
University College London, School of Pharmacy, London, UK.
12
University College London, School of Pharmacy, London, UK; Department of Biochemistry, Aligarh Muslim University, Aligarh, India.
13
Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.
14
Department of Neurointervention, Osaka City General Hospital, Osaka, Japan.
15
Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
16
Department of Neurological Surgery, University of Southern California, Los Angeles, CA, USA.
17
Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
18
Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.
19
Service de Neuroradiologie Diagnostique et Thérapeutique, Hôpital Foch, Suresnes, France.
20
Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
21
Department of Neurointerventional Radiology, Boston Children's Hospital, Boston, MA, USA.
22
Department of Neurosurgery, Boston Children's Hospital, Boston, MA, USA; Department of Neurointerventional Radiology, Boston Children's Hospital, Boston, MA, USA.
23
Department of Genetics, Yale School of Medicine, New Haven, CT, USA; Yale Center for Genome Analysis, West Haven, CT, USA.
24
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
25
Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA; Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. Electronic address: kristopher.kahle@yale.edu.

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

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