Comprehensive multiomic profiling of somatic mutations in malformations of cortical development
Comprehensive multiomic profiling of somatic mutations in malformations of cortical development
Abstract Malformations of cortical development (MCD) are neurological conditions displaying focal disruption of cortical architecture and cellular organization arising during embryogenesis, largely from somatic mosaic mutations. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat epilepsy. Here, we report a genetic atlas from 317 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation and single-cell sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associating distinct pathophysiological and clinical phenotypes. The unique spatiotemporal expression patterns identified by comparing single-nucleus transcriptional sequences of mutated genes in control and patient brains implicates critical roles in excitatory neurogenic pools during brain development, and in promoting neuronal hyperexcitability after birth.
Xu Xin、Urbach Horst、Riley Emily、Wang Yifan、Kim Se Hoon、Kang Hoon-Chul、Schulze-Bonhage Andreas、Gurnett Christina A.、Sattar Shifteh、Nespeca Mark、Imai Katsumi、Chen Robert、Tsai Jin-Wu、Devinsky Orrin、Silva Wilson A. Jr、Machado Helio R.、Baldassari Sara、Brain Somatic Mosaicism Network、Bae Taejeong、Phillips H. Westley、Marsh Ashley P. L.、Breuss Martin W.、Ball Laurel L.、George Renee D.、Barrows Chelsea、Stanley Valentina、Nidhiry Anna、Khoury Sami、Focal Cortical Dysplasia Neurogenetics Consortium、Copeland Brett、Mathern Gary W.、Garcia Camila Ara¨2jo Bernardino、Guerrini Renzo、Vong Keng Ioi、Abyzov Alexej、Gu Jing、Yang Xiaoxu、Takahashi Yukitoshi、Gardner Corrine、Prinz Marco、Howe Gabrielle、Gleeson Joseph G.、Conti Valerio、Mittal Swapnil、Chung Changuk、Xu Mingchu、Donkels Catharina、James Kiely N.、Haas Carola A.、Boulac St¨|phanie、Gonda David D.
Department of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neuroradiology, Medical Center-University of Freiburg, Faculty of MedicineDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Mayo ClinicDiv Pediatric Neurology, Dept of Pediatrics, Severance Children?ˉs Hospital, Yonsei U College of MedicineDiv Pediatric Neurology, Dept of Pediatrics, Severance Children?ˉs Hospital, Yonsei U College of MedicineCenter for Basics in NeuroModulation, Faculty of Medicine, University of FreiburgSt. Louis Children?ˉs Hospital, Washington University St LouisEpilepsy Center, Rady Children?ˉs HospitalEpilepsy Center, Rady Children?ˉs HospitalNational Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological DisordersInstitute of Brain Science, National Yang-Ming UniversityInstitute of Brain Science, National Yang-Ming UniversityEpilepsy Service, Dept. Neurology, New York UniversityDepartment of Genetics, Center for Cell-Based Therapy, Center for Integrative Systems Biology, University of S?o Paulo (USP)Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Dept. of Surgery and Anatomy, University of S?o Paulo (USP)Paris Brain Institute - Institut du Cerveau - ICM, H?pital Piti¨|-Salp¨otri¨¨reDepartment of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Mayo ClinicDepartment of Neurosurgery, University of California at Los AngelesDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San Diego||Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado AuroraDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosurgery, University of California at Los AngelesLaboratory of Pediatric Neurosurgery and Developmental Neuropathology, Dept. of Surgery and Anatomy, University of S?o Paulo (USP)Paediatric Neurology Unit and Laboratories, A. Meyer Children?ˉs Hospital, University of FlorenceDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Mayo ClinicDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoNational Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological DisordersSt. Louis Children?ˉs Hospital, Washington University St LouisCenter for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg||Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of MedicineDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoPaediatric Neurology Unit and Laboratories, A. Meyer Children?ˉs Hospital, University of FlorenceDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of MedicineDepartment of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San DiegoDepartment of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine||Center for Basics in NeuroModulation, Faculty of Medicine, University of FreiburgParis Brain Institute - Institut du Cerveau - ICM, H?pital Piti¨|-Salp¨otri¨¨reEpilepsy Center, Rady Children?ˉs Hospital
神经病学、精神病学基础医学遗传学
epilepsyfocal cortical dysplasiabrain mosaicismmTORsingle-cell sequencingwhole exome sequencing
Xu Xin,Urbach Horst,Riley Emily,Wang Yifan,Kim Se Hoon,Kang Hoon-Chul,Schulze-Bonhage Andreas,Gurnett Christina A.,Sattar Shifteh,Nespeca Mark,Imai Katsumi,Chen Robert,Tsai Jin-Wu,Devinsky Orrin,Silva Wilson A. Jr,Machado Helio R.,Baldassari Sara,Brain Somatic Mosaicism Network,Bae Taejeong,Phillips H. Westley,Marsh Ashley P. L.,Breuss Martin W.,Ball Laurel L.,George Renee D.,Barrows Chelsea,Stanley Valentina,Nidhiry Anna,Khoury Sami,Focal Cortical Dysplasia Neurogenetics Consortium,Copeland Brett,Mathern Gary W.,Garcia Camila Ara¨2jo Bernardino,Guerrini Renzo,Vong Keng Ioi,Abyzov Alexej,Gu Jing,Yang Xiaoxu,Takahashi Yukitoshi,Gardner Corrine,Prinz Marco,Howe Gabrielle,Gleeson Joseph G.,Conti Valerio,Mittal Swapnil,Chung Changuk,Xu Mingchu,Donkels Catharina,James Kiely N.,Haas Carola A.,Boulac St¨|phanie,Gonda David D..Comprehensive multiomic profiling of somatic mutations in malformations of cortical development[EB/OL].(2025-03-28)[2025-05-15].https://www.biorxiv.org/content/10.1101/2022.04.07.487401.点此复制
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