ArticleAmerican journal of human genetics2017
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia.
Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 2 of them syntheses that pooled it.
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Who cites it
114 citing papers in PubMed, 2 syntheses or guidelines pooled it, 206 citations in OpenAlex.
- Customized multigene panels in epilepsy: the best things come in small packages.Neurogenetics · 2020Pooled it
- 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
- Time-Restricted Eating Regimen Differentially Affects Circulatory miRNA Expression in Older Overweight Adults.Nutrients · 2022Trial
- Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.Annals of clinical and translational neurology · 2022Trial
- Somatic mosaicism in the brain: linking development, ageing and neurodegeneration.Nature reviews. Neurology · 2026Review
- Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE): genetics, mechanisms and precision therapy.Acta neuropathologica · 2026Review
- The small molecule simufilam dose-dependently attenuates the worsening of seizures in a mouse model of tuberous sclerosis complex.Epilepsia · 2026Article
- Matched tissue-blood whole-exome sequencing improves detection of genetic etiologies in pediatric drug-resistant epilepsy.Frontiers in pediatrics · 2026Article
- Focal cortical dysplasias: modeling pediatric drug-resistant epilepsy using human brain organoids.Frontiers in cellular neuroscience · 2026Review
- 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
- A CRISPR activation screen reveals a cilia disassembly pathway mutated in focal cortical dysplasia.Science advances · 2025Article
- Alterations in dopaminergic innervation and receptors in focal cortical dysplasia.Brain : a journal of neurology · 2025Article
- Review
- Detecting somatic variants in purified brain DNA obtained from surgically implanted depth electrodes in epilepsy.Epilepsia · 2025Article
- Distant origin of glioblastoma recurrence: neural stem cells in the subventricular zone serve as a source of tumor reconstruction after primary resection.Molecular cancer · 2025Article
- ILAE genetic literacy series: Focal cortical dysplasia.Epileptic disorders : international epilepsy journal with videotape · 2025Review
- Somatic DNA Variants in Epilepsy Surgery Brain Samples from Patients with Lesional Epilepsy.International journal of molecular sciences · 2025Article
- Focal postnatal deletion ofFrontiers in molecular neuroscience · 2025Article
54 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×-20,012×) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.
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