The landscape of epilepsy-related GATOR1 variants
Baldassari, Sara; Picard, Fabienne; Verbeek, Nienke E.; van Kempen, Marjan; Brilstra, Eva H.; Lesca, Gaetan; Conti, Valerio; Guerrini, Renzo; Bisulli, Francesca; Licchetta, Laura; Pippucci, Tommaso; Tinuper, Paolo; Hirsch, Edouard; de Saint Martin, Anne; Chelly, Jamel; Rudolf, Gabrielle; Chipaux, Mathilde; Ferrand-Sorbets, Sarah; Dorfmüller, Georg; Sisodiya, Sanjay; Balestrini, Simona; Schoeler, Natasha; Hernandez-Hernandez, Laura; Krithika, S.; Oegema, Renske; Hagebeuk, Eveline; Gunning, Boudewijn; Deckers, Charles; Berghuis, Bianca; Wegner, Ilse; Niks, Erik; Jansen, Floor E.; Braun, Kees; de Jong, Daniëlle; Rubboli, Guido; Talvik, Inga; Sander, Valentin; Uldall, Peter; Jacquemont, Marie Line; Nava, Caroline; Leguern, Eric; Julia, Sophie; Gambardella, Antonio; d’Orsi, Giuseppe; Crichiutti, Giovanni; Faivre, Laurence; Darmency, Veronique; Benova, Barbora; Krsek, Pavel; Biraben, Arnaud; Lebre, Anne Sophie; Jennesson, Mélanie; Sattar, Shifteh; Marchal, Cécile; Nordli, Douglas R.; Lindstrom, Kristin; Striano, Pasquale; Lomax, Lysa Boissé; Kiss, Courtney; Bartolomei, Fabrice; Lepine, Anne Fabienne; Schoonjans, An Sofie; Stouffs, Katrien; Jansen, Anna; Panagiotakaki, Eleni; Ricard-Mousnier, Brigitte; Thevenon, Julien; de Bellescize, Julitta; Catenoix, Hélène; Dorn, Thomas; Zenker, Martin; Müller-Schlüter, Karen; Brandt, Christian; Krey, Ilona; Polster, Tilman; Wolff, Markus; Balci, Meral; Rostasy, Kevin; Achaz, Guillaume; Zacher, Pia; Becher, Thomas; Cloppenborg, Thomas; Yuskaitis, Christopher J.; Weckhuysen, Sarah; Poduri, Annapurna; Lemke, Johannes R.; Møller, Rikke S.; Baulac, Stéphanie; Baulac, Stéphanie
(2019) Genetics in Medicine, volume 21, issue 2, pp. 398 - 408
(Article)
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
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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.
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Keywords: DEPDC5, Focal cortical dysplasia, Genetic focal epilepsy, mTORC1 pathway, SUDEP, Genetics(clinical)
ISSN: 1098-3600
Publisher: Lippincott Williams and Wilkins
Note: Funding Information: We thank individuals and families for their participation in the study, and clinicians for referring individuals. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. This work was supported by the European Research Council (ERC 682345 to SB), the program “Investissements d’avenir” ANR-10-IAIHU-06, the Fondation Française pour la Recherche sur les Epilepsies. Part of this work was undertaken at University College London Hospitals, with funding from the National Institute for Health Research (NIHR) Biomedical Research Centres funding scheme and the Muir Maxwell Trust and Epilepsy Society, United Kingdom. Publisher Copyright: © 2018, The Author(s).
(Peer reviewed)