Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies

Qaiser, Farah; Yuen, Ryan K. C.; Andrade, Danielle M.

doi:10.1007/s11910-020-01059-x

Cited by 15 publications

(7 citation statements)

References 75 publications

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“…This result substantiates the analysis methods we used. We also found that genes involved in focal epilepsy do not dissociate from those of generalized epilepsy in this network, a result that is not entirely surprising considering other studies which indicated that focal and generalized epilepsies share some underlying genetic causes (Qaiser et al, 2020). Another less likely possibility is that focal epilepsies are caused by mosaic mutations in known generalized epilepsy genes (Myers et al, 2018).…”

Section: Discussionsupporting

confidence: 73%

The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

Fadda

Alsabbagh

Vasudeva

et al. 2022

Preprint

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Epilepsy is one of the most common neurological disorders. The cost to the health system and the impact on quality of life for patients with intractable epilepsies and associated comorbidities is significant. Disease etiology and pathogenesis are still not well understood. Genetic mutations have been shown to be associated with 70% of epilepsies, with the majority being non-monogenic, and the remaining 30% enigmatic. This knowledge gap necessitates further research. The goal of this study is to partially bridge this gap through the genetic analysis of a cohort of patients with epilepsy from an understudied and highly consanguineous population, primarily of ethnicities from the Middle East and North Africa region. Whole exome sequencing was carried out in 81 patients with epilepsy and their family members at a tertiary center in Qatar. We used the data to identify pathogenic variants and type HLA alleles for 13 class I & II genes. We associated the resulting alleles with disease status, using controls of a closely related ethnicity. The genetic yield was approximately 22% for known epilepsy genes. We also suggest a list of 20 genes that could be culprits. Analysis of the biological pathways in which these genes are involved show that focal and generalized epilepsy genes are highly interwound. HLA analysis revealed that class II HLA genes are associated with disease status, particularly DRB4*03:01N, which plays a strong protective role. Our findings suggest that an immune etiology may contribute to the disease together with a genetic culprit, emphasizing the complexity of the etiology of the disease.

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Section: Discussionsupporting

confidence: 73%

The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

Fadda

Alsabbagh

Vasudeva

et al. 2022

Preprint

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“…Germline or somatic mutations, which result in enhanced mTORC1 activity, including in PIK3CA, PTEN, AKT3, TSC1/2, RHEB, and MTOR, are associated with neurodevelopmental disorders with epilepsy (16)(17)(18)(19)(20)(21)(22)(23). Recent studies have also identified mutations in mTORC1 upstream amino acid-sensing GATOR1-KICSTOR-Rag GTPase pathways as a common cause of epilepsy (24), revealing that mutations in GATOR1 (DEPDC5, NPRL2, and NPRL3) (25,26) and KIC-STOR (ITFG2, KPTN, SZT2, and C12ORF66) (6,7,27) genes are often found in epileptic pathologies. The link between the mTORC1 and epilepsy has been recapitulated in animal models with enhanced mTORC1 activity (e.g., Pten +/− , TSC1/2 +/− , and activating mutations in Pik3ca Nestin-Cre knockin (KI), Akt3 KI, MTOR, and Rheb KI) (18,20,23,(28)(29)(30)(31) while inhibition of mTORC1 reversed epileptogenesis in TSC1 GFAP-Cre and Pten +/− mice (20,31).…”

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confidence: 99%

4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Sharma

Sood

Lou

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

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“…This approach has previously identified a ‘two-hit’ phenomenon, where a combination of a germline and a second somatic variant can lead to focal epilepsies. 8 Finally, the two reported TR expansions cannot be classified as there are no guidelines to facilitate pathogenicity interpretation, although these expansions are in the disease range size for other diseases. 53…”

Section: Discussionmentioning

confidence: 99%

“… 4–7 New genetic mechanisms continue to be implicated in both focal and generalized epilepsies. 3 , 8–12 For example, Lennox–Gastaut Syndrome (LGS) is a severe childhood-onset epilepsy syndrome that may be caused by acquired mechanisms (e.g. brain injuries and hypoxic ischaemic lesions), structural abnormalities and/or genetic causes.…”

Section: Introductionmentioning

confidence: 99%

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox–Gastaut syndrome

Qaiser

Sadoway

Yin

et al. 2021

Brain Communications

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Epilepsies are a group of common neurological disorders with a substantial genetic basis. Despite this, the molecular diagnosis of epilepsies remains challenging due to its heterogeneity. Studies utilizing whole genome sequencing may provide additional insights into genetic causes of epilepsies of unknown etiology. Whole genome sequencing was used to evaluate a cohort of adults with unexplained developmental and epileptic encephalopathies (n = 30), for whom prior genetic tests, including whole exome sequencing in some cases, were negative or inconclusive. Rare single nucleotide variants, insertions/deletions, copy number variants and tandem repeat expansions were analyzed. Seven pathogenic or likely pathogenic single nucleotide variants, and two pathogenic deleterious copy number variants were identified in nine patients (32.1% of the cohort). One of the copy number variants, identified in a patient with Lennox-Gastaut syndrome, was too small to be detected by chromosomal microarray techniques. We also identified two tandem repeat expansions with clinical implications in two other patients with Lennox-Gastaut syndrome: a CGG repeat expansion in the 5’untranslated region of DIP2B, and a CTG expansion in ATXN8OS (previously implicated in spinocerebellar ataxia type 8). Three patients had KCNA2 pathogenic variants. One of them died of sudden unexpected death in epilepsy. The other two patients had, in addition to a KCNA2 variant, a second de novo variant impacting potential epilepsy-relevant genes (KCNIP4 and UBR5). Overall, whole genome sequencing provided a genetic explanation in 32.1% of the total cohort. This is also the first report of coding and non-coding tandem repeat expansions identified in patients with Lennox-Gastaut syndrome. This study demonstrates that using whole genome sequencing, the examination of multiple types of rare genetic variation, including those found in the non-coding region of the genome, can help resolve unexplained epilepsies.

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Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies

Cited by 15 publications

References 75 publications

The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Genome sequencing identifies rare tandem repeat expansions and copy number variants in Lennox–Gastaut syndrome

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