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Lee, Semin
Computational Biology Lab.
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Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development

Author(s)
Chung, ChangukYang, XiaoxuBae, TaejeongVong, Keng IoiMittal, Swapnil H.Donkels, CatharinaWestley Phillips, H.Li, ZhenMarsh, Ashley P. L.Breuss, MartinBall, LaurelGarcia, Camila Araujo BernardinoGeorge, ReneeGu, JingXu, MingchuBarrows, ChelseaJames, KielyStanley, ValentinaNidhiry, AnnaKhoury, SamiHowe, GabrielleRiley, EmilyXu, XinCopeland, BrettWang, Yifan G.Kim, Se Hoon L.Kang, Hoon-Chul W.Schulze-Bonhage, AndreasHaas, CarolaUrbach, HorstPrinz, MarcoLimbrick, David A.Gurnett, ChristinaSmyth, Matthew C.Sattar, Shifteh M.Nespeca, Mark B.Gonda, David V.Imai, Katsumi Y.Takahashi, Yukitoshi E.Chen, Hsin-Hung B.Tsai, Jin-WuConti, ValerioGuerrini, RenzoDevinsky, OrrinSilva, WilsonMachado, Helio M.Mathern, GaryAbyzov, AlexejBaldassari, SaraBaulac, StephanieLee, SeminGleeson, Joseph G.
Issued Date
2023-02
DOI
10.1038/s41588-022-01276-9
URI
https://scholarworks.unist.ac.kr/handle/201301/85330
Citation
NATURE GENETICS, v.55, no.2, pp.209 - +
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.
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
Keyword
PATHWAYDIFFERENTIATIONPLASTICITYMIGRATIONEPILEPSYSPECTRUMIMPACTGENE-EXPRESSIONDYSPLASIA

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