ArticleCell reports2017
Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias.
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Article in Cell reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 194 papers, 1 of them a synthesis that pooled it.
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194citing papers in PubMed, 1 pooled it
11.8field-weighted citation impact, top 1% of its field
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Who cites it
194 citing papers in PubMed, 1 synthesis or guideline pooled it, 330 citations in OpenAlex.
- Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery.Brain pathology (Zurich, Switzerland) · 2019Pooled it
- Efficacy and safety of everolimus for patients with focal cortical dysplasia type 2.Epilepsia open · 2025Trial
- Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.Annals of clinical and translational neurology · 2022Trial
- Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion.Brain : a journal of neurology · 2026Article
- Ras-MAPK somatic variants in mesial temporal lobe epilepsy.Current opinion in genetics & development · 2026Review
- Somatic mosaicism in the brain: linking development, ageing and neurodegeneration.Nature reviews. Neurology · 2026Review
- Focal Cortical Dysplasia Type II: Somatic Mutations, Molecular Mechanisms, and Integrative Multi-Omics Framework.CNS neuroscience & therapeutics · 2026Review
- Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.Progress in neuro-psychopharmacology & biological psychiatry · 2026Article
- Cell-type-resolved transcriptomic landscape of human focal cortical dysplasia.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.Stem cell reports · 2026Article
- Epilepsy-associated FOXJ3 variants link a transcriptional program of the PTEN-mTOR pathway to neuronal specification and cortical lamination.Nature communications · 2026Article
- Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy.bioRxiv : the preprint server for biology · 2026Article
- Balloon cells in type II focal cortical dysplasia: developmental origins, molecular signatures, and epileptogenic mechanisms.Frontiers in cell and developmental biology · 2026Review
- Focal cortical dysplasias: modeling pediatric drug-resistant epilepsy using human brain organoids.Frontiers in cellular neuroscience · 2026Review
- Matched tissue-blood whole-exome sequencing improves detection of genetic etiologies in pediatric drug-resistant epilepsy.Frontiers in pediatrics · 2026Article
- Early death and neuronal abnormalities inbioRxiv : the preprint server for biology · 2025Article
- Seizure occurrence in FCD type II is predicted by lesion position and linked to cytoarchitectural alterations.Acta neuropathologica communications · 2025Article
- SLC35A2 loss-of-function variants affect glycomic signatures, neuronal fate and network dynamics.Brain : a journal of neurology · 2025Article
- Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.medRxiv : the preprint server for health sciences · 2025Article
- A CRISPR activation screen reveals a cilia disassembly pathway mutated in focal cortical dysplasia.Science advances · 2025Article
134 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 7 institutions in 2 countries.
Alissa M D'GamaDivision of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Mollie B WoodworthDivision of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Amer A HossainDivision of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Sara BizzottoDivision of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Nicole E HatemDivision of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Christopher M LaCoursiereDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Imad NajmEpilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Zhong YingEpilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA.
Edward YangDepartment of Radiology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
A James BarkovichDepartments of Radiology and Diagnostic Imaging, Neurology, Pediatrics, and Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA.
David J KwiatkowskiBrigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Harry V VintersDepartments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Joseph R MadsenDepartment of Neurosurgery, Boston Children's Hospital, Boston, MA, USA.
Gary W MathernDepartments of Neurosurgery and Psychiatry and Biobehavioral Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Ingmar BlümckeEpilepsy Center, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen, Germany.
Annapurna PoduriDepartment of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA.
Christopher A WalshDivision of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Electronic address: christopher.walsh@childrens.harvard.edu.
Harvard University · USBoston Children's Hospital · USCleveland Clinic · USHoward Hughes Medical Institute · USUniversity of California, Los Angeles · USBroad Institute · USUniversity of California, San Francisco · US
Funding
Medical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MSYNAPTIC MECHANISMS IN HIPPOCAMPAL EPILEPTOGENESISP30HD018655 · NICHD · CHILDREN'S HOSPITAL BOSTON · PI FAGIOLINI, MICHELA · 1985 to 2015
$26.2MUCLA SPORE in Brain CancerP50CA211015 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI David A. Nathanson · 2017 to 2026
$25.2MMolecular, Cellular, & Developmental Dynamics PhD ProgramT32GM007226 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI VAN VACTOR, DAVID L. · 1985 to 2021
$14.4MCell Identity Determination In Human Brain: Somatic Mutation and Cell LineageR01NS032457 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI Alice Eunjung Lee, Christopher A. Walsh · 1995 to 2026
$12.7MHUMAN EPILEPSY GENETICS--NEURONAL MIGRATION DISORDERSR01NS035129 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI WALSH, CHRISTOPHER A. · 1997 to 2023
$9.5M1/2-Somatic mosaicism and autism spectrum disorderU01MH106883 · NIMH · BOSTON CHILDREN'S HOSPITAL · PI PARK, PETER J, WALSH, CHRISTOPHER A. · 2015 to 2019
$9.2MMouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2MPATHOPHYSIOLOGY OF DEVELOPING DYSPLASTIC HUMAN CORTEXR01NS038992 · NINDS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CEPEDA, CARLOS T, MATHERN, GARY W. · 1999 to 2013
$3.3MMolecular characterization of HemimegalencephalyR01NS083823 · NINDS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI GLEESON, JOSEPH G, MATHERN, GARY W. · 2013 to 2017
$3.1MSomatic mutations in epilepsy: whole genome sequence analysis of single neuronsR01NS079277 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI WALSH, CHRISTOPHER A. · 2012 to 2015
$1.4MGenetics of Familial Epilepsy SyndromesK23NS069784 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI PODURI, ANNAPURNA · 2010 to 2014
$901kHoward Hughes Medical InstituteNCI NIH HHS P50 CA211015NICHD NIH HHS P30 HD018655NICHD NIH HHS U54 HD090255NIGMS NIH HHS T32 GM007226NIGMS NIH HHS T32 GM007753NIMH NIH HHS U01 MH106883NINDS NIH HHS K23 NS069784NINDS NIH HHS R01 NS032457NINDS NIH HHS R01 NS035129NINDS NIH HHS R01 NS038992NINDS NIH HHS R01 NS079277NINDS NIH HHS R01 NS083823
Abstract
Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.
Indexed as
Signal TransductionAnimalsCell LineageClass I Phosphatidylinositol 3-KinasesHemimegalencephalyHigh-Throughput Nucleotide SequencingHumansMalformations of Cortical DevelopmentMiceMutationNeuronsStem CellsTelencephalonTOR Serine-Threonine KinasesClass I Phosphatidylinositol 3-KinasesPIK3CA protein, humanTOR Serine-Threonine Kinasesbrain malformationscortical developmentepilepsyexcitatory neuronsfocal cortical dysplasiahemimegalancephalymTOR pathwaynext-generation sequencingsingle-cell sequencingsomatic mutations
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