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

 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 Jr  ;  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 Jr  ;  Helio R Machado  ;  Gary W Mathern  ;  Alexej Abyzov  ;  Sara Baldassari  ;  Stéphanie Baulac  ;  Focal Cortical Dysplasia Neurogenetics Consortium  ;  Brain Somatic Mosaicism Network  ;  Joseph G Gleeson 
 NATURE GENETICS, Vol.55(2) : 209-220, 2023-02 
Journal Title
Issue Date
Brain / metabolism ; Epilepsy* / genetics ; Humans ; Malformations of Cortical Development* / genetics ; Malformations of Cortical Development* / metabolism ; Multiomics ; Mutation ; Related in
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. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
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1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
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