Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Changuk Chung; Xiaoxu Yang; Taejeong Bae; Keng Ioi Vong; Swapnil Mittal; Catharina Donkels; H. Westley Phillips; Zhen Li; Ashley P.L. Marsh; Martin W. Breuss; Laurel L. Ball; Camila Araújo Bernardino Garcia; Renee D. George; Jing Gu; Mingchu Xu; Chelsea Barrows; Kiely N. James; Valentina Stanley; Anna S. Nidhiry; Sami Khoury; Gabrielle Howe; Emily Riley; Xin Xu; Brett Copeland; Yifan Wang; Se Hoon Kim; Hoon-Chul Kang; Andreas Schulze-Bonhage; Carola A. Haas; Horst Urbach; Marco Prinz; David D. Limbrick; Christina A. Gurnett; Matthew D. Smyth; Shifteh Sattar; Mark Nespeca; David D. Gonda; Katsumi Imai; Yukitoshi Takahashi; Hsin-Hung Chen; Jin-Wu Tsai; Valerio Conti; Renzo Guerrini; Orrin Devinsky; Wilson A. Silva; Helio R. Machado; Gary Mathern; Alexej Abyzov; Sara Baldassari; Stéphanie Baulac; Focal Cortical Dysplasia Neurogenetics Consortium; Brain Somatic Mosaicism Network; Jennifer Erwin; Joseph G. Gleeson

doi:10.1038/s41588-022-01276-9

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Changuk Chung
, Xiaoxu Yang
, Taejeong Bae
, Keng Ioi Vong
, Swapnil Mittal
, Catharina Donkels
, H. Westley Phillips
, Zhen Li
, Ashley P.L. Marsh
, Martin W. Breuss
, Laurel L. Ball
, Camila Araújo Bernardino Garcia
, Renee D. George
, Jing Gu
, Mingchu Xu
, Chelsea Barrows
, Kiely N. James
, Valentina Stanley
, Anna S. Nidhiry
, Sami Khoury

Gabrielle Howe, Emily Riley, Xin Xu, Brett Copeland, Yifan Wang, Se Hoon Kim, Hoon-Chul Kang, Andreas Schulze-Bonhage, Carola A. Haas, Horst Urbach, Marco Prinz, David D. Limbrick, Christina A. Gurnett, Matthew D. Smyth, Shifteh Sattar, Mark Nespeca, David D. Gonda, Katsumi Imai, Yukitoshi Takahashi, Hsin-Hung Chen, Jin-Wu Tsai, Valerio Conti, Renzo Guerrini, Orrin Devinsky, Wilson A. Silva, Helio R. Machado, Gary Mathern, Alexej Abyzov, Sara Baldassari, Stéphanie Baulac, Focal Cortical Dysplasia Neurogenetics Consortium, Brain Somatic Mosaicism Network, Jennifer Erwin, Joseph G. Gleeson

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

86 Citations (Scopus)

Abstract

Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

Original language	English
Pages (from-to)	209-220
Number of pages	12
Journal	Nature Genetics
Volume	55
Issue number	2
DOIs	https://doi.org/10.1038/s41588-022-01276-9
Publication status	Published - Feb 2023
Externally published	Yes

Keywords

malformations of cortical development (MCD)
multi-omic profiling
somatic mutations
Cortical development
neurogenesis
Intractable epilepsy

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Chung, C., Yang, X., Bae, T., Vong, K. I., Mittal, S., Donkels, C., Westley Phillips, H., Li, Z., Marsh, A. P. L., Breuss, M. W., Ball, L. L., Garcia, C. A. B., George, R. D., Gu, J., Xu, M., Barrows, C., James, K. N., Stanley, V., Nidhiry, A. S., ... Gleeson, J. G. (2023). Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development. Nature Genetics, 55(2), 209-220. https://doi.org/10.1038/s41588-022-01276-9

@article{c7cfc244c3094921808f48efa7db1e06,

title = "Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development",

abstract = "Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.",

keywords = "malformations of cortical development (MCD), multi-omic profiling, somatic mutations, Cortical development, neurogenesis, Intractable epilepsy",

author = "Changuk Chung and Xiaoxu Yang and Taejeong Bae and Vong, \{Keng Ioi\} and Swapnil Mittal and Catharina Donkels and \{Westley Phillips\}, H. and Zhen Li and Marsh, \{Ashley P.L.\} and Breuss, \{Martin W.\} and Ball, \{Laurel L.\} and Garcia, \{Camila Ara{\'u}jo Bernardino\} and George, \{Renee D.\} and Jing Gu and Mingchu Xu and Chelsea Barrows and James, \{Kiely N.\} and Valentina Stanley and Nidhiry, \{Anna S.\} and Sami Khoury and Gabrielle Howe and Emily Riley and Xin Xu and Brett Copeland and Yifan Wang and Kim, \{Se Hoon\} and Hoon-Chul Kang and Andreas Schulze-Bonhage and Haas, \{Carola A.\} and Horst Urbach and Marco Prinz and Limbrick, \{David D.\} and Gurnett, \{Christina A.\} and Smyth, \{Matthew D.\} and Shifteh Sattar and Mark Nespeca and Gonda, \{David D.\} and Katsumi Imai and Yukitoshi Takahashi and Hsin-Hung Chen and Jin-Wu Tsai and Valerio Conti and Renzo Guerrini and Orrin Devinsky and Silva, \{Wilson A.\} and Machado, \{Helio R.\} and Gary Mathern and Alexej Abyzov and Sara Baldassari and St{\'e}phanie Baulac and \{Focal Cortical Dysplasia Neurogenetics Consortium\} and Gleeson, \{Joseph G.\} and Marilyn Jones and Diane Masser-Frye and Shifteh Sattar and Mark Nespeca and Gonda, \{David D.\} and Katsumi Imai and Yukitoshi Takahashi and Hsin-Hung Chen and Jin-Wu Tsai and Orrin Devinsky and Machado, \{Helio R.\} and Silva, \{Wilson A.\} and Kim, \{Se Hoon\} and Hoon-Chul Kang and Yasemin Alanay and Seema Kapoor and Haas, \{Carola A.\} and Georgia Ramantani and Thomas Feuerstein and Ingmar Blumcke and Robyn Busch and Zhong Ying and Vadym Biloshytsky and Kostiantyn Kostiuk and Eugene Pedachenko and Mathern, \{Gary W.\} and Gurnett, \{Christina A.\} and Ingo Helbig and Kennedy, \{Benjamin C.\} and Judy Liu and Felix Chan and Darcy Krueger and Richard Frye and Angus Wilfong and David Adelson and William Gaillard and Chima Oluigbo and Anne Anderson and \{Brain Somatic Mosaicism Network\} and Alice Lee and Huang, \{August Yue\} and Alissa D{\textquoteright}Gama and Caroline Dias and Walsh, \{Christopher A.\} and Eduardo Maury and Javier Ganz and Michael Lodato and Michael Miller and Pengpeng Li and Rachel Rodin and Rebeca Borges-Monroy and Robert Hill and Sara Bizzotto and Sattar Khoshkhoo and Sonia Kim and Zinan Zhou and Alice Lee and Alison Barton and Alon Galor and Chong Chu and Craig Bohrson and Doga Gulhan and Eduardo Maury and Elaine Lim and Euncheon Lim and Giorgio Melloni and Isidro Cortes and Jake Lee and Joe Luquette and Lixing Yang and Maxwell Sherman and Michael Coulter and Minseok Kwon and Park, \{Peter J.\} and Rebeca Borges-Monroy and Semin Lee and Sonia Kim and Soo Lee and Vinary Viswanadham and Yanmei Dou and Chess, \{Andrew J.\} and Attila Jones and Chaggai Rosenbluh and Schahram Akbarian and Ben Langmead and Jeremy Thorpe and Sean Cho and Andrew Jaffe and Apua Paquola and Weinberger, \{Daniel R.\} and Jennifer Erwin and Jooheon Shin and Michael McConnell and Richard Straub and Rujuta Narurkar and Alexej Abyzov and Yeongjun Jang and Yifan Wang and Anjene Addington and Geetha Senthil and Cindy Molitor and Mette Peters and Gage, \{Fred H.\} and Meiyan Wang and Patrick Reed and Sara Linker and Alexander Urban and Bo Zhou and Reenal Pattni and Xiaowei Zhu and Amero, \{Aitor Serres\} and David Juan and Inna Povolotskaya and Irene Lobon and Moruno, \{Manuel Solis\} and Perez, \{Raquel Garcia\} and Tomas Marques-Bonet and Eduardo Soriano and Gary Mathern and Danny Antaki and Dan Averbuj and Eric Courchesne and Gleeson, \{Joseph G.\} and Ball, \{Laurel L.\} and Breuss, \{Martin W.\} and Subhojit Roy and Xiaoxu Yang and Chen Sun and Flasch, \{Diane A.\} and Trenton, \{Trenton J.Frisbie\} and Kopera, \{Huira C.\} and Kidd, \{Jeffrey M.\} and Moldovan, \{John B.\} and Moran, \{John V.\} and Kwan, \{Kenneth Y.\} and Mills, \{Ryan E.\} and Emery, \{Sarah B.\} and Weichen Zhou and Xuefang Zhao and Aakrosh Ratan and Adriana Cherskov and Alexandre Jourdon and Vaccarino, \{Flora M.\} and Liana Fasching and Nenad Sestan and Sirisha Pochareddy and Soraya Scuder and Gleeson, \{Joseph G.\}",

year = "2023",

month = feb,

doi = "10.1038/s41588-022-01276-9",

language = "English",

volume = "55",

pages = "209--220",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "2",

}

Chung, C, Yang, X, Bae, T, Vong, KI, Mittal, S, Donkels, C, Westley Phillips, H, Li, Z, Marsh, APL, Breuss, MW, Ball, LL, Garcia, CAB, George, RD, Gu, J, Xu, M, Barrows, C, James, KN, Stanley, V, Nidhiry, AS, Khoury, S, Howe, G, Riley, E, Xu, X, Copeland, B, Wang, Y, Kim, SH, Kang, H-C, Schulze-Bonhage, A, Haas, CA, Urbach, H, Prinz, M, Limbrick, DD, Gurnett, CA, Smyth, MD, Sattar, S, Nespeca, M, Gonda, DD, Imai, K, Takahashi, Y, Chen, H-H, Tsai, J-W, Conti, V, Guerrini, R, Devinsky, O, Silva, WA, Machado, HR, Mathern, G, Abyzov, A, Baldassari, S, Baulac, S, Focal Cortical Dysplasia Neurogenetics Consortium, Brain Somatic Mosaicism Network, Erwin, J & Gleeson, JG 2023, 'Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development', Nature Genetics, vol. 55, no. 2, pp. 209-220. https://doi.org/10.1038/s41588-022-01276-9

TY - JOUR

T1 - Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

AU - Chung, Changuk

AU - Yang, Xiaoxu

AU - Bae, Taejeong

AU - Vong, Keng Ioi

AU - Mittal, Swapnil

AU - Donkels, Catharina

AU - Westley Phillips, H.

AU - Li, Zhen

AU - Marsh, Ashley P.L.

AU - Breuss, Martin W.

AU - Ball, Laurel L.

AU - Garcia, Camila Araújo Bernardino

AU - George, Renee D.

AU - Gu, Jing

AU - Xu, Mingchu

AU - Barrows, Chelsea

AU - James, Kiely N.

AU - Stanley, Valentina

AU - Nidhiry, Anna S.

AU - Khoury, Sami

AU - Howe, Gabrielle

AU - Riley, Emily

AU - Xu, Xin

AU - Copeland, Brett

AU - Wang, Yifan

AU - Kim, Se Hoon

AU - Kang, Hoon-Chul

AU - Schulze-Bonhage, Andreas

AU - Haas, Carola A.

AU - Urbach, Horst

AU - Prinz, Marco

AU - Limbrick, David D.

AU - Gurnett, Christina A.

AU - Smyth, Matthew D.

AU - Sattar, Shifteh

AU - Nespeca, Mark

AU - Gonda, David D.

AU - Imai, Katsumi

AU - Takahashi, Yukitoshi

AU - Chen, Hsin-Hung

AU - Tsai, Jin-Wu

AU - Conti, Valerio

AU - Guerrini, Renzo

AU - Devinsky, Orrin

AU - Silva, Wilson A.

AU - Machado, Helio R.

AU - Mathern, Gary

AU - Abyzov, Alexej

AU - Baldassari, Sara

AU - Baulac, Stéphanie

AU - Focal Cortical Dysplasia Neurogenetics Consortium

AU - Gleeson, Joseph G.

AU - Jones, Marilyn

AU - Masser-Frye, Diane

AU - Sattar, Shifteh

AU - Nespeca, Mark

AU - Gonda, David D.

AU - Imai, Katsumi

AU - Takahashi, Yukitoshi

AU - Chen, Hsin-Hung

AU - Tsai, Jin-Wu

AU - Devinsky, Orrin

AU - Machado, Helio R.

AU - Silva, Wilson A.

AU - Kim, Se Hoon

AU - Kang, Hoon-Chul

AU - Alanay, Yasemin

AU - Kapoor, Seema

AU - Haas, Carola A.

AU - Ramantani, Georgia

AU - Feuerstein, Thomas

AU - Blumcke, Ingmar

AU - Busch, Robyn

AU - Ying, Zhong

AU - Biloshytsky, Vadym

AU - Kostiuk, Kostiantyn

AU - Pedachenko, Eugene

AU - Mathern, Gary W.

AU - Gurnett, Christina A.

AU - Helbig, Ingo

AU - Kennedy, Benjamin C.

AU - Liu, Judy

AU - Chan, Felix

AU - Krueger, Darcy

AU - Frye, Richard

AU - Wilfong, Angus

AU - Adelson, David

AU - Gaillard, William

AU - Oluigbo, Chima

AU - Anderson, Anne

AU - Brain Somatic Mosaicism Network

AU - Lee, Alice

AU - Huang, August Yue

AU - D’Gama, Alissa

AU - Dias, Caroline

AU - Walsh, Christopher A.

AU - Maury, Eduardo

AU - Ganz, Javier

AU - Lodato, Michael

AU - Miller, Michael

AU - Li, Pengpeng

AU - Rodin, Rachel

AU - Borges-Monroy, Rebeca

AU - Hill, Robert

AU - Bizzotto, Sara

AU - Khoshkhoo, Sattar

AU - Kim, Sonia

AU - Zhou, Zinan

AU - Lee, Alice

AU - Barton, Alison

AU - Galor, Alon

AU - Chu, Chong

AU - Bohrson, Craig

AU - Gulhan, Doga

AU - Maury, Eduardo

AU - Lim, Elaine

AU - Lim, Euncheon

AU - Melloni, Giorgio

AU - Cortes, Isidro

AU - Lee, Jake

AU - Luquette, Joe

AU - Yang, Lixing

AU - Sherman, Maxwell

AU - Coulter, Michael

AU - Kwon, Minseok

AU - Park, Peter J.

AU - Borges-Monroy, Rebeca

AU - Lee, Semin

AU - Kim, Sonia

AU - Lee, Soo

AU - Viswanadham, Vinary

AU - Dou, Yanmei

AU - Chess, Andrew J.

AU - Jones, Attila

AU - Rosenbluh, Chaggai

AU - Akbarian, Schahram

AU - Langmead, Ben

AU - Thorpe, Jeremy

AU - Cho, Sean

AU - Jaffe, Andrew

AU - Paquola, Apua

AU - Weinberger, Daniel R.

AU - Erwin, Jennifer

AU - Shin, Jooheon

AU - McConnell, Michael

AU - Straub, Richard

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AU - Abyzov, Alexej

AU - Jang, Yeongjun

AU - Wang, Yifan

AU - Addington, Anjene

AU - Senthil, Geetha

AU - Molitor, Cindy

AU - Peters, Mette

AU - Gage, Fred H.

AU - Wang, Meiyan

AU - Reed, Patrick

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AU - Zhou, Bo

AU - Pattni, Reenal

AU - Zhu, Xiaowei

AU - Amero, Aitor Serres

AU - Juan, David

AU - Povolotskaya, Inna

AU - Lobon, Irene

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AU - Perez, Raquel Garcia

AU - Marques-Bonet, Tomas

AU - Soriano, Eduardo

AU - Mathern, Gary

AU - Antaki, Danny

AU - Averbuj, Dan

AU - Courchesne, Eric

AU - Gleeson, Joseph G.

AU - Ball, Laurel L.

AU - Breuss, Martin W.

AU - Roy, Subhojit

AU - Yang, Xiaoxu

AU - Sun, Chen

AU - Flasch, Diane A.

AU - Trenton, Trenton J.Frisbie

AU - Kopera, Huira C.

AU - Kidd, Jeffrey M.

AU - Moldovan, John B.

AU - Moran, John V.

AU - Kwan, Kenneth Y.

AU - Mills, Ryan E.

AU - Emery, Sarah B.

AU - Zhou, Weichen

AU - Zhao, Xuefang

AU - Ratan, Aakrosh

AU - Cherskov, Adriana

AU - Jourdon, Alexandre

AU - Vaccarino, Flora M.

AU - Fasching, Liana

AU - Sestan, Nenad

AU - Pochareddy, Sirisha

AU - Scuder, Soraya

AU - Gleeson, Joseph G.

PY - 2023/2

Y1 - 2023/2

N2 - Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

AB - Malformations of cortical development (MCD) are neurological conditions involving focal disruptions of cortical architecture and cellular organization that arise during embryogenesis, largely from somatic mosaic mutations, and cause intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype–phenotype correlation analysis elucidated specific MCD gene sets associated with distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains indicate critical roles in excitatory neurogenic pools during brain development and in promoting neuronal hyperexcitability after birth.

KW - malformations of cortical development (MCD)

KW - multi-omic profiling

KW - somatic mutations

KW - Cortical development

KW - neurogenesis

KW - Intractable epilepsy

UR - https://www.scopus.com/pages/publications/85146225741

U2 - 10.1038/s41588-022-01276-9

DO - 10.1038/s41588-022-01276-9

M3 - Article

C2 - 36635388

AN - SCOPUS:85146225741

SN - 1061-4036

VL - 55

SP - 209

EP - 220

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

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