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 & 27 others 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)429-443.e4
JournalNeuron
Volume101
Issue number3
DOIs
StatePublished - Feb 6 2019

Fingerprint

Vein of Galen Malformations
Ephrins
Chromatin
Mutation
Genes
Blood Vessels
Brain
Skin Abnormalities
Modifier Genes
Exome
Penetrance
Veins
Arteries
Genome

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Duran, D., Zeng, X., Jin, S. C., Choi, J., Nelson-Williams, C., Yatsula, B., ... 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

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

In: Neuron, Vol. 101, No. 3, 06.02.2019, p. 429-443.e4.

Research output: Contribution to journalArticle

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
Duran D, Zeng X, Jin SC, Choi J, Nelson-Williams C, Yatsula B et al. Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation. Neuron. 2019 Feb 6;101(3):429-443.e4. https://doi.org/10.1016/j.neuron.2018.11.041
Duran, Daniel ; Zeng, Xue ; Jin, Sheng Chih ; Choi, Jungmin ; Nelson-Williams, Carol ; Yatsula, Bogdan ; Gaillard, Jonathan ; Furey, Charuta Gavankar ; Lu, Qiongshi ; Timberlake, Andrew T. ; Dong, Weilai ; Sorscher, Michelle A. ; Loring, Erin ; Klein, Jennifer ; Allocco, August ; Hunt, Ava ; Conine, Sierra ; Karimy, Jason K. ; Youngblood, Mark W. ; Zhang, Jinwei ; DiLuna, Michael L. ; Matouk, Charles C. ; Mane, Shrikant ; Tikhonova, Irina R. ; Castaldi, Christopher ; López-Giráldez, Francesc ; Knight, James ; Haider, Shozeb ; Soban, Mariya ; Alper, Seth L. ; Komiyama, Masaki ; Ducruet, Andrew F. ; Zabramski, Joseph M. ; Dardik, Alan ; Walcott, Brian P. ; Stapleton, Christopher J. ; Aagaard-Kienitz, Beverly ; Rodesch, Georges ; Jackson, Eric ; Smith, Edward R. ; Orbach, Darren B. ; Berenstein, Alejandro ; Bilguvar, Kaya ; Vikkula, Miikka ; Gunel, Murat ; Lifton, Richard P. ; Kahle, Kristopher T. / Mutations in Chromatin Modifier and Ephrin Signaling Genes in Vein of Galen Malformation. In: Neuron. 2019 ; Vol. 101, No. 3. pp. 429-443.e4.
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