The landscape of epilepsy-related GATOR1 variants

Sara Baldassari (1, 2) , Fabienne Picard , Nienke E. 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 (2, 1) , Eric E. Leguern (2, 1) , Sophie Julia (14) , Antonio Gambardella , Giuseppe D’orsi , Giovanni Crichiutti , Laurence Faivre (15, 16, 17) , Véronique Darmency (18) , Barbora Benova , Pavel Krsek , Arnaud Biraben (19) , Anne Lebre , Mélanie Jennesson , Shifteh Sattar , Cécile Marchal , Douglas Nordli , Kristin Lindstrom , Pasquale Striano , Lysa Boissé Lomax , Courtney Kiss , Fabrice Bartolomei (20) , Fabienne Lepine , An-Sofie Schoonjans , Katrien Stouffs , Anna Jansen , Eleni Panagiotakaki (21) , Brigitte Ricard-Mousnier , Julien Thevenon (22, 16, 23) , Julitta de Bellescize (24) , Hélène Catenoix (24) , Thomas Dorn , Martin Zenker (25) , Karen Müller-Schlüter , Christian Brandt , Ilona Krey , Tilman Polster , Markus Wolff , Meral Balci , Kevin Rostasy , Guillaume Achaz (26, 27) , Pia Zacher , Thomas Becher , Thomas Cloppenborg , Christopher Yuskaitis , Sara Weckhuysen , Anna Poduri , Johannes Lemke , S. Møller (12) , Stéphanie Baulac (1, 2)

1 ICM - Institut du Cerveau = Paris Brain Institute
2 CHU Pitié-Salpêtrière [AP-HP]
3 Department of Genetics [Utrecht, the Netherlands]
4 University Medical Center [Utrecht]
5 Service de Génétique [HCL Groupement Hospitalier Est]
6 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
7 Children's Hospital A. Meyer
8 Service de Neurologie [Strasbourg]
9 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
10 Department of Clinical and Experimental Epilepsy
11 Academic Center for Epileptology Kempenhaeghe & Maastricht UMC+ [Heeze]
12 Danish Epilepsy Centre
13 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
14 Service Génétique Médicale [CHU Toulouse]
15 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
16 FHU TRANSLAD (CHU de Dijon)
17 UB - Université de Bourgogne
18 Service de Neurophysiologie Clinique (CHU Dijon)
19 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
20 Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM]
21 Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques
22 Equipe GAD (LNC - U1231)
23 UBFC - Université Bourgogne Franche-Comté [COMUE]
24 Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon]
25 Institute of Human Genetics
26 ISYEB - Institut de Systématique, Evolution, Biodiversité
27 CIRB - Centre interdisciplinaire de recherche en biologie

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.

Mots clés: DEPDC5; mTORC1 pathway; genetic focal epilepsy; focal cortical dysplasia; SUDEP

Domaines: Génétique humaine

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