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

Autor:	Chung C; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Yang X; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Bae T; Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Vong KI; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Mittal S; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Donkels C; Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Westley Phillips H; Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, USA., Li Z; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Marsh APL; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Breuss MW; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado Aurora, Aurora, CO, USA., Ball LL; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Garcia CAB; Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Department of Surgery and Anatomy, University of São Paulo, Ribeirão Preto, Brazil., George RD; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; 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.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Xu M; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; 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.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., James KN; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Stanley V; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Nidhiry AS; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Khoury S; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Howe G; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Riley E; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Xu X; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.; 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.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA., Wang Y; Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Kim SH; Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea., Kang HC; Division of Pediatric Neurology, Department of Pediatrics, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, South Korea., Schulze-Bonhage A; Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Haas CA; Department of Neurosurgery, Experimental Epilepsy Research, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Urbach H; Department of Neuroradiology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany., Prinz M; Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany., Limbrick DD Jr; Department of Neurology, St. Louis Children's Hospital, Washington University St Louis, Washington, MO, USA., Gurnett CA; Department of Neurology, St. Louis Children's Hospital, Washington University St Louis, Washington, MO, USA., Smyth MD; Department of Neurosurgery, St. Louis Children's Hospital, Washington University St Louis, Washington, MO, USA., Sattar S; Epilepsy Center, Rady Children's Hospital, San Diego, CA, USA., Nespeca M; Epilepsy Center, Rady Children's Hospital, San Diego, CA, USA., Gonda DD; Epilepsy Center, Rady Children's Hospital, San Diego, CA, USA., Imai K; National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan., Takahashi Y; National Epilepsy Center, NHO Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, Japan., Chen HH; Division of Pediatric Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, Taipei City, Taiwan., Tsai JW; Institute of Brain Science, Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan., Conti V; Pediatric Neurology Unit and Laboratories, IRCCS Meyer Children's Hospital University of Florence, Firenze, Italy., Guerrini R; Pediatric Neurology Unit and Laboratories, IRCCS Meyer Children's Hospital University of Florence, Firenze, Italy., Devinsky O; Comprehensive Epilepsy Center, Department of Neurology, New York University Langone Health, New York, NY, USA., Silva WA Jr; Department of Genetics, Center for Cell-Based Therapy, Center for Integrative Systems Biology, University of São Paulo, Ribeirão Preto, Brazil., Machado HR; Laboratory of Pediatric Neurosurgery and Developmental Neuropathology, Department of Surgery and Anatomy, University of São Paulo, Ribeirão Preto, Brazil., Mathern GW; Department of Neurosurgery, University of California at Los Angeles, Los Angeles, CA, USA., Abyzov A; Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA., Baldassari S; Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France., Baulac S; Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, Paris, France., Gleeson JG; Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. jogleeson@health.ucsd.edu.; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. jogleeson@health.ucsd.edu.
Jazyk:	angličtina
Zdroj:	Nature genetics [Nat Genet] 2023 Feb; Vol. 55 (2), pp. 209-220. Date of Electronic Publication: 2023 Jan 12.
DOI:	10.1038/s41588-022-01276-9
Abstrakt:	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.)
Databáze:	MEDLINE
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