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The landscape of epilepsy-related GATOR1 variants

Sara Baldassari 1, 2 Fabienne Picard Nienke Verbeek 3 Marjan van Kempen 4 Eva Brilstra 4 Gaetan Lesca 5, 6 Valerio Conti 7 Renzo Guerrini 7 Francesca Bisulli Laura Licchetta Tommaso Pippucci Paolo Tinuper Edouard Hirsch 8 Anne de Saint Martin Jamel Chelly 9 Gabrielle Rudolf 9 Mathilde Chipaux Sara Ferrand-Sorbets Georg Dorfmüller Sanjay Sisodiya 10 Simona Balestrini Natasha Schoeler Laura Hernandez-Hernandez 10 S. Krithika Renske Oegema 3 Eveline Hagebeuk Boudewijn Gunning Charles Deckers Bianca Berghuis Ilse Wegner Erik Niks Floor Jansen Kees Braun Danielle de Jong 11 Guido Rubboli Inga Talvik Valentin Sander Peter Uldall 12 Marie-Line Jacquemont 13 Caroline Nava 14, 1 Eric Leguern 14, 1 Sophie Julia 15 Antonio Gambardella Giuseppe D’orsi Giovanni Crichiutti Laurence Faivre 16, 17, 18 Véronique Darmency 19 Barbora Benova Pavel Krsek Arnaud Biraben 20 Anne Lebre Mélanie Jennesson Shifteh Sattar Cécile Marchal Douglas Nordli Kristin Lindstrom Pasquale Striano Lysa Boissé Lomax Courtney Kiss Fabrice Bartolomei 21 Fabienne Lepine An-Sofie Schoonjans Katrien Stouffs Anna Jansen Eleni Panagiotakaki 22 Brigitte Ricard-Mousnier Julien Thevenon 23, 17, 24 Julitta de Bellescize 25 Hélène Catenoix 25 Thomas Dorn Martin Zenker 26 Karen Müller-Schlüter Christian Brandt Ilona Krey Tilman Polster Markus Wolff Meral Balci Kevin Rostasy Guillaume Achaz 27 Pia Zacher Thomas Becher Thomas Cloppenborg Christopher Yuskaitis Sara Weckhuysen Anna Poduri Johannes Lemke S. Møller 12 Stéphanie Baulac 1, 2, *
* Auteur correspondant
23 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
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.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-02063270
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : lundi 11 mars 2019 - 09:40:34
Dernière modification le : mercredi 14 octobre 2020 - 04:06:16

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Sara Baldassari, Fabienne Picard, Nienke Verbeek, Marjan van Kempen, Eva Brilstra, et al.. The landscape of epilepsy-related GATOR1 variants. Genetics in Medicine, Nature Publishing Group, 2019, 21 (2), pp.398-408. ⟨10.1038/s41436-018-0060-2⟩. ⟨hal-02063270⟩

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