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

Daniel Duran; Xue Zeng; Sheng Chih Jin; Jungmin Choi; Carol Nelson-Williams; Bogdan Yatsula; Jonathan Gaillard; Charuta Gavankar Furey; Qiongshi Lu; Andrew T. Timberlake; Weilai Dong; Michelle A. Sorscher; Erin Loring; Jennifer Klein; August Allocco; Ava Hunt; Sierra Conine; Jason K. Karimy; Mark W. Youngblood; Jinwei Zhang; Michael L. DiLuna; Charles C. Matouk; Shrikant Mane; Irina R. Tikhonova; Christopher Castaldi; Francesc López-Giráldez; James Knight; Shozeb Haider; Mariya Soban; Seth L. Alper; Masaki Komiyama; Andrew F. Ducruet; Joseph M. Zabramski; Alan Dardik; Brian P. Walcott; Christopher J. Stapleton; Beverly Aagaard-Kienitz; Georges Rodesch; Eric Jackson; Edward R. Smith; Darren B. Orbach; Alejandro Berenstein; Kaya Bilguvar; Miikka Vikkula; Murat Gunel; Richard P. Lifton; Kristopher T. Kahle

doi:10.1016/j.neuron.2018.11.041

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

Daniel Duran, Xue Zeng, Sheng Chih Jin, Jungmin Choi, Carol Nelson-Williams, Bogdan Yatsula, Jonathan Gaillard, Charuta Gavankar Furey, Qiongshi Lu, Andrew T. Timberlake, Weilai Dong, Michelle A. Sorscher, Erin Loring, Jennifer Klein, August Allocco, Ava Hunt, Sierra Conine, Jason K. Karimy, Mark W. Youngblood, Jinwei ZhangMichael L. DiLuna, Charles C. Matouk, Shrikant Mane, Irina R. Tikhonova, Christopher Castaldi, Francesc López-Giráldez, James Knight, Shozeb Haider, Mariya Soban, Seth L. Alper, Masaki Komiyama, Andrew F. Ducruet, Joseph M. Zabramski, Alan Dardik, Brian P. Walcott, Christopher J. Stapleton, Beverly Aagaard-Kienitz, Georges Rodesch, Eric Jackson, Edward R. Smith, Darren B. Orbach, Alejandro Berenstein, Kaya Bilguvar, Miikka Vikkula, Murat Gunel, Richard P. Lifton, Kristopher T. Kahle

School of Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English (US)
Pages (from-to)	429-443.e4
Journal	Neuron
Volume	101
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2018.11.041
State	Published - Feb 6 2019

Keywords

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

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2018.11.041

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Duran, D., Zeng, X., Jin, S. C., Choi, J., Nelson-Williams, C., Yatsula, B., Gaillard, J., Furey, C. G., Lu, Q., Timberlake, A. T., Dong, W., Sorscher, M. A., Loring, E., Klein, J., Allocco, A., Hunt, A., Conine, S., Karimy, J. K., Youngblood, M. W., ... Kahle, K. T. (2019). Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation. Neuron, 101(3), 429-443.e4. https://doi.org/10.1016/j.neuron.2018.11.041

Duran, D, Zeng, X, Jin, SC, Choi, J, Nelson-Williams, C, Yatsula, B, Gaillard, J, Furey, CG, Lu, Q, Timberlake, AT, Dong, W, Sorscher, MA, Loring, E, Klein, J, Allocco, A, Hunt, A, Conine, S, Karimy, JK, Youngblood, MW, Zhang, J, DiLuna, ML, Matouk, CC, Mane, S, Tikhonova, IR, Castaldi, C, López-Giráldez, F, Knight, J, Haider, S, Soban, M, Alper, SL, Komiyama, M, Ducruet, AF, Zabramski, JM, Dardik, A, Walcott, BP, Stapleton, CJ, Aagaard-Kienitz, B, Rodesch, G, Jackson, E, Smith, ER, Orbach, DB, Berenstein, A, Bilguvar, K, Vikkula, M, Gunel, M, Lifton, RP & Kahle, KT 2019, 'Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation', Neuron, vol. 101, no. 3, pp. 429-443.e4. https://doi.org/10.1016/j.neuron.2018.11.041

@article{3070808522eb4f33bdcfc6b549e39fee,

title = "Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation",

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",

author = "Daniel Duran and Xue Zeng and Jin, {Sheng Chih} and Jungmin Choi and Carol Nelson-Williams and Bogdan Yatsula and Jonathan Gaillard and Furey, {Charuta Gavankar} and Qiongshi Lu and Timberlake, {Andrew T.} and Weilai Dong and Sorscher, {Michelle A.} and Erin Loring and Jennifer Klein and August Allocco and Ava Hunt and Sierra Conine and Karimy, {Jason K.} and Youngblood, {Mark W.} and Jinwei Zhang and DiLuna, {Michael L.} and Matouk, {Charles C.} and Shrikant Mane and Tikhonova, {Irina R.} and Christopher Castaldi and Francesc L{\'o}pez-Gir{\'a}ldez and James Knight and Shozeb Haider and Mariya Soban and Alper, {Seth L.} and Masaki Komiyama and Ducruet, {Andrew F.} and Zabramski, {Joseph M.} and Alan Dardik and Walcott, {Brian P.} and Stapleton, {Christopher J.} and Beverly Aagaard-Kienitz and Georges Rodesch and Eric Jackson and Smith, {Edward R.} and Orbach, {Darren B.} and Alejandro Berenstein and Kaya Bilguvar and Miikka Vikkula and Murat Gunel and Lifton, {Richard P.} and Kahle, {Kristopher T.}",

note = "Funding Information: We thank the patients and families who participated in this research. We acknowledge support from the Yale-NIH Center for Mendelian Genomics ( 5U54HG006504 ) and an NIH NRCDP award to K.T.K. S.C.J. was supported by a James Hudson Brown-Alexander Brown Coxe postdoctoral fellowship and an American Heart Association postdoctoral fellowship. J.G. was supported by a Howard Hughes Institute medical research fellowship. Last, we acknowledge Collin Whitmore and his family for their inspiration, courage, and generous support. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = feb,

day = "6",

doi = "10.1016/j.neuron.2018.11.041",

language = "English (US)",

volume = "101",

pages = "429--443.e4",

journal = "Neuron",

issn = "0896-6273",

publisher = "Cell Press",

number = "3",

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TY - JOUR

T1 - Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation

AU - Duran, Daniel

AU - Zeng, Xue

AU - Jin, Sheng Chih

AU - Choi, Jungmin

AU - Nelson-Williams, Carol

AU - Yatsula, Bogdan

AU - Gaillard, Jonathan

AU - Furey, Charuta Gavankar

AU - Lu, Qiongshi

AU - Timberlake, Andrew T.

AU - Dong, Weilai

AU - Sorscher, Michelle A.

AU - Loring, Erin

AU - Klein, Jennifer

AU - Allocco, August

AU - Hunt, Ava

AU - Conine, Sierra

AU - Karimy, Jason K.

AU - Youngblood, Mark W.

AU - Zhang, Jinwei

AU - DiLuna, Michael L.

AU - Matouk, Charles C.

AU - Mane, Shrikant

AU - Tikhonova, Irina R.

AU - Castaldi, Christopher

AU - López-Giráldez, Francesc

AU - Knight, James

AU - Haider, Shozeb

AU - Soban, Mariya

AU - Alper, Seth L.

AU - Komiyama, Masaki

AU - Ducruet, Andrew F.

AU - Zabramski, Joseph M.

AU - Dardik, Alan

AU - Walcott, Brian P.

AU - Stapleton, Christopher J.

AU - Aagaard-Kienitz, Beverly

AU - Rodesch, Georges

AU - Jackson, Eric

AU - Smith, Edward R.

AU - Orbach, Darren B.

AU - Berenstein, Alejandro

AU - Bilguvar, Kaya

AU - Vikkula, Miikka

AU - Gunel, Murat

AU - Lifton, Richard P.

AU - Kahle, Kristopher T.

N1 - Funding Information: We thank the patients and families who participated in this research. We acknowledge support from the Yale-NIH Center for Mendelian Genomics ( 5U54HG006504 ) and an NIH NRCDP award to K.T.K. S.C.J. was supported by a James Hudson Brown-Alexander Brown Coxe postdoctoral fellowship and an American Heart Association postdoctoral fellowship. J.G. was supported by a Howard Hughes Institute medical research fellowship. Last, we acknowledge Collin Whitmore and his family for their inspiration, courage, and generous support. Publisher Copyright: © 2018 Elsevier Inc.

PY - 2019/2/6

Y1 - 2019/2/6

N2 - 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.

AB - 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.

KW - EPHB4

KW - Vein of Galen malformation

KW - arterio-venous malformation

KW - chromatin modifier

KW - de novo mutations

KW - ephrin signaling

KW - pediatric neurosurgery

KW - whole exome sequencing

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UR - http://www.scopus.com/inward/citedby.url?scp=85060867676&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2018.11.041

DO - 10.1016/j.neuron.2018.11.041

M3 - Article

C2 - 30578106

AN - SCOPUS:85060867676

SN - 0896-6273

VL - 101

SP - 429-443.e4

JO - Neuron

JF - Neuron

IS - 3

ER -

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

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Keywords

ASJC Scopus subject areas

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