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

Focal Cortical Dysplasia Neurogenetics Consortium; Brain Somatic Mosaicism Network

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

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

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 - 2023 Feb 1

Bibliographical note

Funding Information:
AmpliSeq, TASeq and snRNA-seq were supported by NIH P30CA023100 and S10OD026929 at the UCSD IGM Genomics Center. Rady Children’s Institute for Genomic Medicine, Broad Institute (U54HG003067, UM1HG008900), the Yale Center for Mendelian Disorders (U54HG006504) and the New York Genome Center provided WES. The UCSD Microscopy Core (NINDS P30NS047101) provided imaging support. The UCSD Tissue Technology Shared Resources Team (National Cancer Institute Cancer Center Support Grant, P30CA23100) supported paraffin sectioning and H&E staining. This study was supported by the 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (30598 to C.C.), NIH (NIMH U01MH108898 and R01MH124890 to J.G.G. and G.W.M. and NIA R21AG070462, NINDS R01NS083823 to J.G.G.), the Regione Toscana under the Call for Health 2018 (DECODE-EE to R.G.) and Fondazione Cassa di Risparmio di Firenze (to R.G.). Figures 1b and 3a were created with BioRender.com. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.

Funding Information:
AmpliSeq, TASeq and snRNA-seq were supported by NIH P30CA023100 and S10OD026929 at the UCSD IGM Genomics Center. Rady Children’s Institute for Genomic Medicine, Broad Institute (U54HG003067, UM1HG008900), the Yale Center for Mendelian Disorders (U54HG006504) and the New York Genome Center provided WES. The UCSD Microscopy Core (NINDS P30NS047101) provided imaging support. The UCSD Tissue Technology Shared Resources Team (National Cancer Institute Cancer Center Support Grant, P30CA23100) supported paraffin sectioning and H&E staining. This study was supported by the 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (30598 to C.C.), NIH (NIMH U01MH108898 and R01MH124890 to J.G.G. and G.W.M. and NIA R21AG070462, NINDS R01NS083823 to J.G.G.), the Regione Toscana under the Call for Health 2018 (DECODE-EE to R.G.) and Fondazione Cassa di Risparmio di Firenze (to R.G.). Figures and were created with BioRender.com . The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

All Science Journal Classification (ASJC) codes

Genetics

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10.1038/s41588-022-01276-9

Cite this

@article{a7b5d88d00ad4cc39eeb97f522d474a8,

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 Kang, {Hoon Chul} 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 Chen, {Hsin Hung} and Tsai, {Jin Wu} 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",

note = "Funding Information: AmpliSeq, TASeq and snRNA-seq were supported by NIH P30CA023100 and S10OD026929 at the UCSD IGM Genomics Center. Rady Children{\textquoteright}s Institute for Genomic Medicine, Broad Institute (U54HG003067, UM1HG008900), the Yale Center for Mendelian Disorders (U54HG006504) and the New York Genome Center provided WES. The UCSD Microscopy Core (NINDS P30NS047101) provided imaging support. The UCSD Tissue Technology Shared Resources Team (National Cancer Institute Cancer Center Support Grant, P30CA23100) supported paraffin sectioning and H&E staining. This study was supported by the 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (30598 to C.C.), NIH (NIMH U01MH108898 and R01MH124890 to J.G.G. and G.W.M. and NIA R21AG070462, NINDS R01NS083823 to J.G.G.), the Regione Toscana under the Call for Health 2018 (DECODE-EE to R.G.) and Fondazione Cassa di Risparmio di Firenze (to R.G.). Figures 1b and 3a were created with BioRender.com. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. Funding Information: AmpliSeq, TASeq and snRNA-seq were supported by NIH P30CA023100 and S10OD026929 at the UCSD IGM Genomics Center. Rady Children{\textquoteright}s Institute for Genomic Medicine, Broad Institute (U54HG003067, UM1HG008900), the Yale Center for Mendelian Disorders (U54HG006504) and the New York Genome Center provided WES. The UCSD Microscopy Core (NINDS P30NS047101) provided imaging support. The UCSD Tissue Technology Shared Resources Team (National Cancer Institute Cancer Center Support Grant, P30CA23100) supported paraffin sectioning and H&E staining. This study was supported by the 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (30598 to C.C.), NIH (NIMH U01MH108898 and R01MH124890 to J.G.G. and G.W.M. and NIA R21AG070462, NINDS R01NS083823 to J.G.G.), the Regione Toscana under the Call for Health 2018 (DECODE-EE to R.G.) and Fondazione Cassa di Risparmio di Firenze (to R.G.). Figures and were created with BioRender.com . The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = feb,

day = "1",

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",

}

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

N1 - Funding Information: AmpliSeq, TASeq and snRNA-seq were supported by NIH P30CA023100 and S10OD026929 at the UCSD IGM Genomics Center. Rady Children’s Institute for Genomic Medicine, Broad Institute (U54HG003067, UM1HG008900), the Yale Center for Mendelian Disorders (U54HG006504) and the New York Genome Center provided WES. The UCSD Microscopy Core (NINDS P30NS047101) provided imaging support. The UCSD Tissue Technology Shared Resources Team (National Cancer Institute Cancer Center Support Grant, P30CA23100) supported paraffin sectioning and H&E staining. This study was supported by the 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (30598 to C.C.), NIH (NIMH U01MH108898 and R01MH124890 to J.G.G. and G.W.M. and NIA R21AG070462, NINDS R01NS083823 to J.G.G.), the Regione Toscana under the Call for Health 2018 (DECODE-EE to R.G.) and Fondazione Cassa di Risparmio di Firenze (to R.G.). Figures 1b and 3a were created with BioRender.com. The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. Funding Information: AmpliSeq, TASeq and snRNA-seq were supported by NIH P30CA023100 and S10OD026929 at the UCSD IGM Genomics Center. Rady Children’s Institute for Genomic Medicine, Broad Institute (U54HG003067, UM1HG008900), the Yale Center for Mendelian Disorders (U54HG006504) and the New York Genome Center provided WES. The UCSD Microscopy Core (NINDS P30NS047101) provided imaging support. The UCSD Tissue Technology Shared Resources Team (National Cancer Institute Cancer Center Support Grant, P30CA23100) supported paraffin sectioning and H&E staining. This study was supported by the 2021 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (30598 to C.C.), NIH (NIMH U01MH108898 and R01MH124890 to J.G.G. and G.W.M. and NIA R21AG070462, NINDS R01NS083823 to J.G.G.), the Regione Toscana under the Call for Health 2018 (DECODE-EE to R.G.) and Fondazione Cassa di Risparmio di Firenze (to R.G.). Figures and were created with BioRender.com . The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2023/2/1

Y1 - 2023/2/1

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.

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JF - Nature Genetics

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ER -

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

Abstract

Bibliographical note

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