The landscape of epilepsy-related GATOR1 variants

Baldassari, Sara and Picard, Fabienne and Verbeek, Nienke E. and van Kempen, Marjan and Brilstra, Eva H. and Lesca, Gaetan and Conti, Valerio and Guerrini, Renzo and Bisulli, Francesca and Licchetta, Laura and Pippucci, Tommaso and Tinuper, Paolo and Hirsch, Edouard and de Saint Martin, Anne and Chelly, Jamel and Rudolf, Gabrielle and Chipaux, Mathilde and Ferrand-Sorbets, Sarah and Dorfmüller, Georg and Sisodiya, Sanjay and Balestrini, Simona and Schoeler, Natasha and Hernandez-Hernandez, Laura and Krithika, S. and Oegema, Renske and Hagebeuk, Eveline and Gunning, Boudewijn and Deckers, Charles and Berghuis, Bianca and Wegner, Ilse and Niks, Erik and Jansen, Floor E. and Braun, Kees and de Jong, Daniëlle and Rubboli, Guido and Talvik, Inga and Sander, Valentin and Uldall, Peter and Jacquemont, Marie-Line and Nava, Caroline and Leguern, Eric and Julia, Sophie and Gambardella, Antonio and d’Orsi, Giuseppe and Crichiutti, Giovanni and Faivre, Laurence and Darmency, Veronique and Benova, Barbora and Krsek, Pavel and Biraben, Arnaud and Lebre, Anne-Sophie and Jennesson, Mélanie and Sattar, Shifteh and Marchal, Cécile and Nordli, Douglas R. and Lindstrom, Kristin and Striano, Pasquale and Lomax, Lysa B. and Kiss, Courtney and Bartolomei, Fabrice and Lepine, Anne F. and Schoonjans, An-Sofie and Stouffs, Katrien and Jansen, Anna and Panagiotakaki, Eleni and Ricard-Mousnier, Brigitte and Thevenon, Julien and de Bellescize, Julitta and Catenoix, Hélène and Dorn, Thomas and Zenker, Martin and Müller-Schlüter, Karen and Brandt, Christian and Krey, Ilona and Polster, Tilman and Wolff, Markus and Balci, Meral and Rostasy, Kevin and Achaz, Guillaume and Zacher, Pia and Becher, Thomas and Cloppenborg, Thomas and Yuskaitis, Christopher J. and Weckhuysen, Sarah and Poduri, Annapurna and Lemke, Johannes R. and Møller, Rikke S. and Baulac, Stéphanie (2019) The landscape of epilepsy-related GATOR1 variants. Genetics in Medicine, 21 (2). pp. 398-408. ISSN 1530-0366

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Official URL: https://doi.org/10.1038/s41436-018-0060-2

Abstract

Purpose: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway. Methods: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. Results: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. Conclusion: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Item Type: Journal Article
Keywords: DEPDC5, mTORC1 pathway, Genetic focal epilepsy, Focal cortical dysplasia, SUDEP
Faculty: ARCHIVED Faculty of Science & Technology (until September 2018)
Depositing User: Lisa Blanshard
Date Deposited: 30 Jul 2020 14:04
Last Modified: 20 Jan 2021 11:37
URI: https://arro.anglia.ac.uk/id/eprint/705737

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