Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes

Krenn, Martin; Wagner, Matias; Hotzy, Christoph; Graf, Elisabeth; Weber, Sandrina; Brunet, Theresa; Lorenz‐Depiereux, Bettina; Kasprian, Gregor; Aull‐Watschinger, Susanne; Pataraia, Ekaterina; Stögmann, Elisabeth; Zimprich, Alexander; Strom, Tim M.; Meitinger, Thomas; Zimprich, Fritz

doi:10.1136/jmedgenet-2019-106658

Cited by 19 publications

(23 citation statements)

References 42 publications

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“…4,5 Whole-exome sequencing (WES) case-control studies have led to multiple insights into the epilepsies, such as the contribution of de novo variants in developmental and epileptic encephalopathy (DEE [MIM: 308350]), the role of the GABA pathway in genetic generalized epilepsy (GGE [MIM: 600669]), and the link between non-acquired focal epilepsy (NAFE [MIM: 604364, 245570]) and GATOR1 complex genes. [6][7][8][9][10] DEEs are a severe form of early onset, intractable epilepsy associated with developmental delay. 8,[11][12][13][14] In contrast, GGE and NAFE, characterized by generalized seizures and focal seizures, respectively, are more common and generally less severe.…”

Section: Introductionmentioning

confidence: 99%

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Collaborative¹

2021

The American Journal of Human Genetics

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Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEEaffected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

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Section: Introductionmentioning

confidence: 99%

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Collaborative¹

2021

The American Journal of Human Genetics

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“…Pathogenic or likely pathogenic variants in the DEPDC5, NPRL2 and NPRL3 genes were identified in 8–11% of individuals within focal epilepsy cohorts, mostly comprised of familial non-lesional cases. 3 , 4 , 63 The frequency of GATOR1-related epilepsies in these studies is likely over-estimates of their true prevalence due to the enrichment of familial cases in the cohorts. Large international collaborative studies have demonstrated the contribution of ultra-rare variation in known epilepsy genes to common epilepsies, like non-acquired focal epilepsy.…”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 96%

“… 11 Seizures usually begin in childhood or adolescence but the age of first seizure has ranged from the first days of life to older than 50 years. 3 , 11 , 63 , 111 Importantly, over half of individuals with GATOR1-related epilepsies have DRE ( Table 3 ). 11 …”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

“… 1 , 2 Evidence is now emerging for a significant monogenic contribution to the focal epilepsies. 3 , 4 Genetic data increasingly inform clinical decision-making. Our enhanced understanding of the molecular mechanisms underpinning some monogenic epilepsies has prompted repurposing of existing drugs that target specific genetic mechanisms and development of novel precision therapies.…”

Section: Introductionmentioning

confidence: 99%

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Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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The mechanistic target of rapamycin (mTOR) signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mTOR cascade funnels through mTOR complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mTOR complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mTOR regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mTOR pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mTOR complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively the mTORopathies are characterised by excessive mTOR pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically-mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalised medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mTOR pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mTOR inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.

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“…1,2 However, molecular diagnostic rates with genomic sequencing vary across testing indications, 3 and may also differ substantially between patients with the same disease entity depending on individual phenotypic factors. [4][5][6][7] There is a clinically and economically grounded need to identify patients who are more likely to carry pathogenic DNA variation detectable by genomic sequencing, and therefore would be more likely to benefit from such testing. 8,9 Recently, we took advantage of a very large collection of whole-exome sequencing (WES) data from patients with dystonia to isolate clinical variables significantly associated with diagnostic outcome; these included (i) an onset of dystonia before the age of 21 years, (ii) a manifestation of segmental or generalized dystonia, and (iii) a combination of dystonia with non-dystonic neurological features (other movement disorders and/or non-movement disorder-related symptoms).…”

Section: Introductionmentioning

confidence: 99%

Scoring Algorithm‐Based Genomic Testing in Dystonia: A Prospective Validation Study

et al. 2021

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Despite the limitations, including a short follow-up period and small sample size, this pilot study suggests that FUS Vo-thalamotomy may be an alternative treatment option for patients with FHD. A randomized controlled study with a larger sample size and a longer follow-up period is warranted to elucidate the efficacy and safety of MRgFUS Vo-thalamotomy for FHD.Acknowledgments: We thank Kaoru Shimizu from the Intelligent Clinical Research and Innovation Center at the Tokyo Women's Medical University for her invaluable assistance in the conduct of this study.

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Diagnostic exome sequencing in non-acquired focal epilepsies highlights a major role of GATOR1 complex genes

Cited by 19 publications

References 42 publications

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Epilepsy in the mTORopathies: opportunities for precision medicine

Scoring Algorithm‐Based Genomic Testing in Dystonia: A Prospective Validation Study

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