Comprehensive multiomic profiling of somatic mutations in malformations of cortical development
Xu Xin 1Urbach Horst 2Riley Emily 1Wang Yifan 3Kim Se Hoon 4Kang Hoon-Chul 4Schulze-Bonhage Andreas 5Gurnett Christina A. 6Sattar Shifteh 7Nespeca Mark 7Imai Katsumi 8Chen Robert 9Tsai Jin-Wu 9Devinsky Orrin 10Silva Wilson A. Jr 11Machado Helio R. 12Baldassari Sara 13Brain Somatic Mosaicism Network Bae Taejeong 3Phillips H. Westley 14Marsh Ashley P. L. 1Breuss Martin W. 15Ball Laurel L. 1George Renee D. 1Barrows Chelsea 1Stanley Valentina 1Nidhiry Anna 1Khoury Sami 1Focal Cortical Dysplasia Neurogenetics Consortium Copeland Brett 1Mathern Gary W. 14Garcia Camila Ara¨2jo Bernardino 12Guerrini Renzo 16Vong Keng Ioi 1Abyzov Alexej 3Gu Jing 1Yang Xiaoxu 1Takahashi Yukitoshi 8Gardner Corrine 6Prinz Marco 17Howe Gabrielle 1Gleeson Joseph G. 1Conti Valerio 16Mittal Swapnil 1Chung Changuk 1Xu Mingchu 1Donkels Catharina 18James Kiely N. 1Haas Carola A. 19Boulac St¨|phanie 13Gonda David D.7
作者信息
- 1. Department of Neurosciences, University of California San Diego||Rady Children?ˉs Institute for Genomic Medicine, San Diego
- 2. Department of Neuroradiology, Medical Center-University of Freiburg, Faculty of Medicine
- 3. Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Mayo Clinic
- 4. Div Pediatric Neurology, Dept of Pediatrics, Severance Children?ˉs Hospital, Yonsei U College of Medicine
- 5. Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg
- 6. St. Louis Children?ˉs Hospital, Washington University St Louis
- 7. Epilepsy Center, Rady Children?ˉs Hospital
- 8. National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders
- 9. Institute of Brain Science, National Yang-Ming University
- 10. Epilepsy Service, Dept. Neurology, New York University
- 11. Department of Genetics, Center for Cell-Based Therapy, Center for Integrative Systems Biology, University of S?o Paulo (USP)
- 12. Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Dept. of Surgery and Anatomy, University of S?o Paulo (USP)
- 13. Paris Brain Institute - Institut du Cerveau - ICM, H?pital Piti¨|-Salp¨otri¨¨re
- 14. Department of Neurosurgery, University of California at Los Angeles
- 15. Department 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 Aurora
- 16. Paediatric Neurology Unit and Laboratories, A. Meyer Children?ˉs Hospital, University of Florence
- 17. Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg||Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine
- 18. Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine
- 19. Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine||Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg
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Abstract
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.Key words
epilepsy/focal cortical dysplasia/brain mosaicism/mTOR/single-cell sequencing/whole exome sequencing引用本文复制引用
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)[2026-06-17].https://www.biorxiv.org/content/10.1101/2022.04.07.487401.学科分类
神经病学、精神病学/基础医学/遗传学
