Somatic mutations involving TSC 1 and TSC2 genes in two children with focal cortical dysplasia

Jha, Ruchika; Kurup, Arjun; Kovilapu, Uday Bhanu; Ranjan, Rakesh; Sondhi, Vishal

doi:10.1016/j.braindev.2021.10.002

Cited by 7 publications

(4 citation statements)

References 31 publications

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“…In particular, FCD 2 is associated with genetic variants in the crucial mTOR‐ GATOR pathway. Due to the limitations of most studies using conventional WES, deep targeted gene sequencing (>500×) (Baldassari et al, 2019 ; Jansen et al, 2015 ; Kumari et al, 2020 ; Moller et al, 2016 ; Sim et al, 2019 ; Zhang et al, 2020 ), or deep WES for few FCD 2 patients (Bennett et al, 2022 ; Jha et al, 2022 ; Nakashima et al, 2015 ; Zhao et al, 2019 ), the associated causative genes for FCD 2 may not be fully discovered. In this study, for 11 FCD patients with core lesion and peripheral blood, we identified the DEPDC5 germline variant in a patient with FCD 2A; ATK3 , MTOR , and MED12 somatic variants in three FCD 2A patients and TSC2 somatic variant in an FCD 2B patient through deep whole‐exome sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, more than 60 cases with FCD 2 have been reported to have pathogenic or potentially deleterious somatic variants in the above genes, and the MTOR and TSC1/2 somatic variants were the most common, accounting for about 75%. The variant allele frequencies (VAFs) in FCD 2 ranged from 0.25% to 15.6%, and more than 15% were TSC1/2 somatic variants, VAFs ranged from 1.4% to 50.1% (Baldassari et al, 2019 ; Bennett et al, 2022 ; Blumcke et al, 2021 ; Jansen et al, 2015 ; Jha et al, 2022 ; Kumari et al, 2020 ; Lee et al, 2020 ; Moller et al, 2016 ; Nakashima et al, 2015 ; Sim et al, 2019 ; Zhang et al, 2020 ; Zhao et al, 2019 ). In our study, we found that cases 2 and 4 with FCD 2A had somatic variants in AKT3 and MTOR genes, case 8 with FCD 2B had somatic variants in TSC2 gene, and the VAFs were 5.12%, 3.66%, and 2.52%, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole‐exome sequencing

Zhao

Wang

et al. 2022

Molec Gen & Gen Med

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Background:Objective Focal cortical dysplasia type 2 (FCD2) is malformations of cortical development that constitutes a common cause of pediatric focal epilepsy. Germline or somatic variants in the mammalian target of rapamycin (mTOR) signaling pathway genes are pathogenesis of FCD2. In this study, whole-exome deep sequencing was performed on dysplastic cortex from focal epilepsy in children to explore genetic characteristic in FCD2. MethodsResected core lesions of FCD2 were con rmed by pathology and peripheral blood from 11 patients were collected. Deep whole-exome sequencing (> 500X) was performed on derived genomic DNA, germline or somatic variants in brainspeci c genes were analyzed and identi ed. ResultsIn 11 patients, a heterozygous pathogenic germline variant of DEPDC5 was identi ed in one case, while somatic variants were found in four brain samples. The frequencies of the somatic variant allele were 2.52%~5.12%. Somatic variants in AKT3, TSC2 and MTOR (mTOR signaling pathway genes) were found in three samples. Besides, one somatic variant was detected in MED12 which not been reported to associated with FCD2. ConclusionOur study expanded the variant spectrum in the mTOR-GATOR pathway, also detected a somatic variant in MED12 which was potentially associated with FCD 2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole‐exome sequencing

Zhao

Wang

et al. 2022

Molec Gen & Gen Med

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“…In utero Tsc1/2 knockdown also increased the number of axons in developing cortical neurons (Choi et al, 2008). Importantly, recent reports suggest that loss of TSC genes through a Two Hit mechanism can also cause FCD (D'Gama et al, 2017;Lim et al, 2017;Baldassari et al, 2019b;Jha et al, 2022;Chung et al, 2023). In utero electroporation of CRISPR-Cas9 system targeting TSC genes was used to model the FCD which produced cortical dyslamination, cytomegalic neurons, and induced seizures (Lim et al, 2017).Taken together, TSC1/TSC2 somatic mutations within TSC or FCD patients can cause malformations in the cortex that often underlie seizures.…”

Section: Mouse Models Of Tscmentioning

confidence: 99%

Modeling genetic mosaicism of the mammalian target of rapamycin pathway in the cerebral cortex

Feliciano

2023

Front. Mamm. Sci.

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The capacity to integrate complex sensory cues and to coordinate an adequate behavioral response often requires integration of information within the outermost part of the mammalian brain called the cerebral cortex. The laminar and columnar cytoarchitecture of the cerebral cortex contains neurons that establish proximal and distal connections. Genetically encoded transcription factors ensure the generation of the appropriate number, types, locations, and connections of cortical neurons. However, somatic mutations that alter cortical development provide evidence that post-transcriptional regulation is equally important. An example is that somatic mutations in regulators and substrates of mammalian target of rapamycin (mTOR) are associated with neuropsychiatric and neurological manifestations. mTOR is a protein kinase that phosphorylates substrates that control mRNA translation and anabolic processes. Numerous challenges remain in uncovering the mechanisms by which mutations in regulators and substrates of mTOR impact behavior. Here, evidence is provided that somatic mosaicism can be modeled in the developing murine cerebral cortex which may have clinical significance.

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“…Furthermore, target approaches identified specific somatic brain variants in some pathologies, such as the forme fruste of Sturge-Weber syndrome (SWS) [45]. Different case reports showed similar results [36,47,49,[51][52][53]57,58].…”

Section: Somatic Variants In the Brain And Refractory Epilepsiesmentioning

confidence: 99%

CfDNA Measurement as a Diagnostic Tool for the Detection of Brain Somatic Mutations in Refractory Epilepsy

Mayo

Gómez-Manjón

Fernández-Martínez

et al. 2022

IJMS

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Epilepsy is a neurological disorder that affects more than 50 million people. Its etiology is unknown in approximately 60% of cases, although the existence of a genetic factor is estimated in about 75% of these individuals. Hundreds of genes involved in epilepsy are known, and their number is increasing progressively, especially with next-generation sequencing techniques. However, there are still many cases in which the results of these molecular studies do not fully explain the phenotype of the patients. Somatic mutations specific to brain tissue could contribute to the phenotypic spectrum of epilepsy. Undetectable in the genomic DNA of blood cells, these alterations can be identified in cell-free DNA (cfDNA). We aim to review the current literature regarding the detection of somatic variants in cfDNA to diagnose refractory epilepsy, highlighting novel research directions and suggesting further studies.

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Somatic mutations involving TSC 1 and TSC2 genes in two children with focal cortical dysplasia

Cited by 7 publications

References 31 publications

Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole‐exome sequencing

Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole‐exome sequencing

Modeling genetic mosaicism of the mammalian target of rapamycin pathway in the cerebral cortex

CfDNA Measurement as a Diagnostic Tool for the Detection of Brain Somatic Mutations in Refractory Epilepsy

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