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

Focal Cortical Dysplasia Neurogenetics Consortium; Brain Somatic Mosaicism Network; 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 W. Mathern; Alexej Abyzov; Sara Baldassari; Stéphanie Baulac; Joseph G. Gleeson

doi:10.1038/s41588-022-01276-9

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

Focal Cortical Dysplasia Neurogenetics Consortium, Brain Somatic Mosaicism Network, 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 StanleyAnna 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 W. Mathern, Alexej Abyzov, Sara Baldassari, Stéphanie Baulac, Joseph G. Gleeson

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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
Early online date	12 Jan 2023
DOIs	https://doi.org/10.1038/s41588-022-01276-9
Publication status	Published - Feb 2023

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Focal Cortical Dysplasia Neurogenetics Consortium, Brain Somatic Mosaicism Network, 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., ... 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{107a4510274646b6b2ceb9b94a29d1cd,

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.",

author = "{Focal Cortical Dysplasia Neurogenetics Consortium} and {Brain Somatic Mosaicism Network} and 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 Mathern, {Gary W.} and Alexej Abyzov and Sara Baldassari and St{\'e}phanie Baulac and Gleeson, {Joseph G.} and Felix Chan",

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 Publishing Group",

number = "2",

}

Focal Cortical Dysplasia Neurogenetics Consortium, Brain Somatic Mosaicism Network, 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, GW, Abyzov, A, Baldassari, S, Baulac, S & 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 - Focal Cortical Dysplasia Neurogenetics Consortium

AU - Brain Somatic Mosaicism Network

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 W.

AU - Abyzov, Alexej

AU - Baldassari, Sara

AU - Baulac, Stéphanie

AU - Gleeson, Joseph G.

AU - Chan, Felix

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.

U2 - 10.1038/s41588-022-01276-9

DO - 10.1038/s41588-022-01276-9

M3 - Article

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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