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Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.
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, 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, Wilson A; Machado, Helio R; Mathern, Gary W; Abyzov, Alexej; Baldassari, Sara; Baulac, Stéphanie.
Affiliation
  • Chung C; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Yang X; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Bae T; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Vong KI; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Mittal S; Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • Donkels C; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Westley Phillips H; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Li Z; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Marsh APL; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Breuss MW; Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Ball LL; Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, USA.
  • Garcia CAB; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • George RD; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Gu J; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Xu M; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Barrows C; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • James KN; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Stanley V; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Aurora, Aurora, CO, USA.
  • Nidhiry AS; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Khoury S; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Howe G; Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Department of Surgery and Anatomy, University of São Paulo, Ribeirão Preto, Brazil.
  • Riley E; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Xu X; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Copeland B; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Wang Y; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Kim SH; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Kang HC; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Schulze-Bonhage A; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Haas CA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Urbach H; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Prinz M; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Limbrick DD; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Gurnett CA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Smyth MD; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Sattar S; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Nespeca M; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Gonda DD; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Imai K; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Takahashi Y; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Chen HH; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Tsai JW; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Conti V; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Guerrini R; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Devinsky O; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
  • Silva WA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • Machado HR; Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • Mathern GW; Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea.
  • Abyzov A; Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, South Korea.
  • Baldassari S; Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Baulac S; Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Nat Genet ; 55(2): 209-220, 2023 02.
Article de En | MEDLINE | ID: mdl-36635388
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.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Épilepsie / Malformations corticales Limites: Humans Langue: En Journal: Nat Genet Sujet du journal: GENETICA MEDICA Année: 2023 Type de document: Article Pays d'affiliation: États-Unis d'Amérique
Texte intégral
Ajouter à My VHL
Imprimer
XML
PubMed Links
Recherche sur Google

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Épilepsie / Malformations corticales Limites: Humans Langue: En Journal: Nat Genet Sujet du journal: GENETICA MEDICA Année: 2023 Type de document: Article Pays d'affiliation: États-Unis d'Amérique