| Genet Med. 2018 Aug 10. doi: 10.1038/s41436-018-0060-2. [Epub ahead of print]
The landscape of epilepsy-related GATOR1 variants.
Baldassari S1,2,3,4,5, Picard F6, Verbeek NE7, van Kempen M7, Brilstra EH7, Lesca G8, Conti V9, Guerrini R9, Bisulli F10, Licchetta L10, Pippucci T11, Tinuper P10, Hirsch E12, de Saint Martin A13, Chelly J14, Rudolf G14, Chipaux M15, Ferrand-Sorbets S15, Dorfmüller G15, Sisodiya S16, Balestrini S16, Schoeler N16, Hernandez-Hernandez L16, Krithika S16, Oegema R7, Hagebeuk E17, Gunning B17, Deckers C17, Berghuis B17, Wegner I17, Niks E18, Jansen FE19, Braun K19, de Jong D20, Rubboli G21, Talvik I22, Sander V22, Uldall P23, Jacquemont ML24, Nava C1,2,3,4,5, Leguern E1,2,3,4,5, Julia S25, Gambardella A26, d'Orsi G27, Crichiutti G28, Faivre L29, Darmency V30, Benova B31, Krsek P31, Biraben A32, Lebre AS33, Jennesson M34, Sattar S35, Marchal C36, Nordli DR Jr37, Lindstrom K38, Striano P39, Lomax LB40,41, Kiss C41, Bartolomei F42, Lepine AF42, Schoonjans AS43, Stouffs K44, Jansen A44, Panagiotakaki E45, Ricard-Mousnier B46, Thevenon J47, de Bellescize J45, Catenoix H45, Dorn T48, Zenker M49, Müller-Schlüter K50, Brandt C51, Krey I52, Polster T51, Wolff M53, Balci M54, Rostasy K54, Achaz G55, Zacher P56, Becher T57, Cloppenborg T51, Yuskaitis CJ58,59,60, Weckhuysen S61, Poduri A58,59,60, Lemke JR52, Møller RS62, Baulac S63,64,65,66,67, Baulac S1,2,3,4,5. Author information 1Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.2INSERM, U1127, F-75013, Paris, France.3CNRS, UMR 7225, F-75013, Paris, France.4Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.5Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.6Department of Clinical Neurosciences, University Hospitals and Medical School of Geneva, Geneva, Switzerland.7Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.8Service de Génétique, Hospices Civils de Lyon - GHE; CNRS UMR 5292, INSERM U1028, CNRL, et Université Claude Bernard Lyon 1, GHE, Lyon, France.9Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, A. Meyer Children's Hospital, Florence, Italy.10IRCCS, Istituto delle Scienze Neurologiche of Bologna; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.11Medical Genetics Unit, Polyclinic Sant' Orsola-Malpighi University Hospital, Bologna, Italy.12Department of Neurology-centre de référence des épilepsies rares, University Hospital of Strasbourg, Strasbourg, France.13Department of Pediatrics - centre de référence des épilepsies rares, University Hospital of Strasbourg, Strasbourg, France.14IGBMC, INSERM, CNRS, Strasbourg University, Strasbourg, France.15Department of Pediatric Neurosurgery, Fondation Rothschild, F-75019, Paris, France.16Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.17Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.18Leiden University Medical Center, Leiden, The Netherlands.19Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.20Department of Neurology, Academic Center for Epileptology Kempenhaeghe, Heeze, The Netherlands.21Danish Epilepsy Centre, Dianalund, University of Copenhagen, Copenhagen, Denmark.22Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia.23Danish Epilepsy Centre, Dianalund, Denmark.24Unit of Medical Genetics, CHU La Réunion, Saint Pierre, F-97448, France.25Service de Génétique Médicale, Pavillon Lefebvre, Hôpital Purpan CHU Toulouse, Toulouse, France.26Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.27Epilepsy Center, Clinic of Nervous System Diseases, University of Foggia, Riuniti Hospital, Foggia, Italy.28Department of Pediatrics, Institute of Medicine, University Hospital of Udine, Udine, Italy.29Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, CHU de Dijon et Université de Bourgogne, Dijon, France.30Service de neurophysiologie et pédiatrie 1, CHU de Dijon, Dijon, France.31Department of Paediatric Neurology, Motol University Hospital, 2nd faculty of medicine Charles University, Prague, Czech Republic.32Centre Hospitalier Universitaire de Rennes, F-35000, Rennes, France.33CHU Reims, Hôpital Maison Blanche, Pôle de Biologie, Service de Génétique, Reims, F-51092, France.34CHU Reims, American Memorial Hospital, Service de Pédiatrie, REIMS, F-51092, France.35Department of Pediatric Neurology, Rady Children's Hospital/University of California, San Diego, California, USA.36Service d'Epileptologie Clinique, CHU de Bordeaux, France.37Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.38Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, USA.39Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, Genova, Italy.40Department of Medicine, Divisions of Neurology and Respirology, Queen's University, Kingston, Ontario, Canada.41Kingston Health Sciences Centre, Kingston, Ontario, K7L 2V7, Canada.42Pediatric Neurology Department, Timone Hospital, APHM, Marseille, France.43Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium.44Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Neurogenetics Research Group, Laarbeeklaan 101, 1090, Brussels, Belgium.45Paediatric Clinical Epileptology, Sleep disorders and Functional Neurology, University Hospitals of Lyon (HCL), Lyon, France.46Unité d'épileptologie, Service de Neurologie, CHU, 49033, Angers, France.47Inserm UMR 1231 GAD Team, Genetics of Developmental Anomalies, et FHU-TRANSLAD, CHU/Université de Bourgogne-Franche Comté, Dijon, France.48Clinique Bernoise, Crans-, Montana, Switzerland.49Institute of Human Genetics, University Hospital, Magdeburg, Germany.50Epilepsy Center for Children, Brandenburg Medical School, University Hospital, Neuruppin, Germany.51Bethel Epilepsy Centre, Bielefeld, Germany.52Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.53Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.54Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany.55Institut de Systématique, Evolution, Biodiversité, ISYEB, UMR 7205 CNRS MNHN UPMC EPHE, Paris, France.56The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany.57Kinderneurologisches Zentrum, Düsseldorf-Gerresheim, Sana Kliniken, Düsseldorf, Germany.58Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.59Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Boston, Massachusetts, USA.60Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.61Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.62Danish Epilepsy Centre, Dianalund; Institute for Regional Health research, University of Southern Denmark, Odense, Denmark.63Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France. [email protected], U1127, F-75013, Paris, France. [email protected], UMR 7225, F-75013, Paris, France. [email protected] du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France. [email protected] of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, F-75013, Paris, France. [email protected]. 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. https://www.ncbi.nlm.nih.gov/pubmed/?term=...GATOR1+variants
SCOPO:
Per definire lo spettro fenotipico e mutazionale delle epilessie correlate ai geni DEPDC5, NPRL2 e NPRL3 che codificano il complesso GATOR1, un regolatore negativo del percorso mTORC1 METODI: Abbiamo analizzato i dati clinici e genetici di 73 nuovi probandi (familiari e sporadici) con epilessia correlata varianti nei geni codificanti GATOR1 e nuove linee guida proposte per l'interpretazione clinica delle varianti di GATOR1.
RISULTATI:
Il fenotipo convulsivo GATOR1 consisteva principalmente in crisi focali (ad es. Ipermotoria o convulsioni del lobo frontale nel 50%), con età media all'esordio di 4,4 anni, spesso correlata al sonno e resistente ai farmaci (54%) e associata a corticostero focale displasia (20%). Spasmi infantili sono stati segnalati nel 10% dei probandi. La morte improvvisa improvvisa nell'epilessia (SUDEP) si è verificata nel 10% delle famiglie. Un nuovo quadro di classificazione di tutte le 140 varianti di GATOR1 correlate all'epilessia (incluse le varianti di questo studio) ha rivelato che il 68% è patogeno con perdita di funzione, il 14% è probabilmente patogeno, il 15% sono varianti di significato incerto e il 3% è probabile .
CONCLUSIONE:
I nostri dati sottolineano il ruolo sempre più importante dei geni GATOR1 nella patogenesi delle epilessie focali (> 180 probandi fino ad oggi). Lo spettro fenotipico GATOR1 spazia dalle epilessie sporadiche ad esordio precoce con comorbidità cognitive a comorbilità epilettiche familiari e SUDEP. https://translate.google.it/?hl=it&tab=TT
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