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

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• dc.contributor.author Chung, Changuk
• dc.contributor.author Brain Somatic Mosaicism Network
• dc.contributor.author Gleeson, Joseph G.
• dc.date.accessioned 2023-09-28T06:20:45Z
• dc.date.available 2023-09-28T06:20:45Z
• dc.date.issued 2023
• dc.description.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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Chung C, Yang X, Bae T, Vong KI, Mittal S, Donkels C, et al. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development. Nat Genet. 2023 Feb;55(2):209-20. DOI: 10.1038/s41588-022-01276-9
• dc.identifier.doi http://dx.doi.org/10.1038/s41588-022-01276-9
• dc.identifier.issn 1061-4036
• dc.identifier.uri http://hdl.handle.net/10230/57986
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Genet. 2023 Feb;55(2):209-20
• dc.rights © Springer Nature Publishing AG [Chung C, Yang X, Bae T, Vong KI, Mittal S, Donkels C, et al. Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development. Nat Genet. 2023 Feb;55(2):209-20. DOI: 10.1038/s41588-022-01276-9] [http://dx.doi.org/10.1038/s41588-022-01276-9]
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Genetics research
• dc.subject.keyword Neurogenesis
• dc.title Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion