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

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 bee...

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Published inNature genetics Vol. 55; no. 2; pp. 209 - 220
Main Authors Chung, Changuk, Yang, Xiaoxu, Bae, Taejeong, Vong, Keng Ioi, Mittal, Swapnil, Donkels, Catharina, Westley Phillips, H, Li, Zhen, Marsh, Ashley P L, Breuss, Martin W, Ball, Laurel L, Garcia, Camila Araújo Bernardino, George, Renee D, Gu, Jing, Xu, Mingchu, Barrows, Chelsea, James, Kiely N, Stanley, Valentina, Nidhiry, Anna S, Khoury, Sami, Howe, Gabrielle, Riley, Emily, Xu, Xin, Copeland, Brett, Wang, Yifan, Kim, Se Hoon, Kang, Hoon-Chul, Schulze-Bonhage, Andreas, Haas, Carola A, Urbach, Horst, Prinz, Marco, Limbrick, Jr, David D, Gurnett, Christina A, Smyth, Matthew D, Sattar, Shifteh, Nespeca, Mark, Gonda, David D, Imai, Katsumi, Takahashi, Yukitoshi, Chen, Hsin-Hung, Tsai, Jin-Wu, Conti, Valerio, Guerrini, Renzo, Devinsky, Orrin, Silva, Jr, Wilson A, Machado, Helio R, Mathern, Gary W, Abyzov, Alexej, Baldassari, Sara, Baulac, Stéphanie, Gleeson, Joseph G
Format Journal Article
LanguageEnglish
Published United States Nature Publishing Group 01.02.2023
Subjects
Brain
Brain - metabolism
Brain cancer
Candidates
Correlation analysis
Electroporation
Embryogenesis
Embryonic growth stage
Epilepsy
Epilepsy - genetics
Gene expression
Gene sequencing
Genes
Genotypes
Humans
Kinases
Life Sciences
Malformations of Cortical Development
Malformations of Cortical Development - genetics
Malformations of Cortical Development - metabolism
MCD gene
Multiomics
Mutation
Phenotypes
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Summary: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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PMCID: PMC9961399
Full membership of the FCD Neurogenetic Consortium is listed at the end of this file
C.C., X.Y., Sa.B., St.B., and J.G.G. designed the study. C.C., S.M., and S.K. conducted functional validation. C.B., V.S., A.S.N., E.R., C.C., and G.H. coordinated the clinical database. X.Y., C.C., M.W.B., L.L.B., R.D.G., J.G., M.X., A.P.L.M., and K.N.J. organized, handled, and sequenced human samples. X.Y., C.C., T.B., Y.W., A.A., X.X., Z.L., and B.C. performed bioinformatics and data analysis. C.C. and K.I.V. performed the RNAscope experiment. C.D., H.W.P., C.A.B.G., S.H.K., H.K., H.U., M.P., A.S., C.A.H., D.D.L., C.A.G., M.D.S., S.S., M.N., D.D.G., K.I., Y.T., H.C., J.T., V.C., R.G., O.D., W.A.S., H.R.M., and G.W.M. provided resected brain tissues and clinical data from FCD patients. C.C., X.Y., and J.G.G. wrote the manuscript. All authors read and commented on the manuscript before submission.
Full membership of the Brain Somatic Mosaicism Network is listed at the end of this file
These authors contributed equally
Author contributions
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-022-01276-9