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.

Bethel Epilepsy Centre Bielefeld Germany

Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD CHU de Dijon et Université de Bourgogne Dijon France

Centre Hospitalier Universitaire de Rennes F 35000 Rennes France

Children's Hospital Los Angeles Keck School of Medicine University of Southern California Los Angeles California USA

CHU Reims American Memorial Hospital Service de Pédiatrie REIMS F 51092 France

CHU Reims Hôpital Maison Blanche Pôle de Biologie Service de Génétique Reims F 51092 France

Clinique Bernoise Crans Montana Switzerland

CNRS UMR 7225 F 75013 Paris France

Danish Epilepsy Centre Dianalund Denmark

Danish Epilepsy Centre Dianalund University of Copenhagen Copenhagen Denmark

Danish Epilepsy Centre Dianalund; Institute for Regional Health research University of Southern Denmark Odense Denmark

Department of Child Neurology Brain Center Rudolf Magnus University Medical Center Utrecht The Netherlands

Department of Clinical and Experimental Epilepsy UCL Institute of Neurology WC1N 3BG and Chalfont Centre for Epilepsy Bucks UK

Department of Clinical Neurosciences University Hospitals and Medical School of Geneva Geneva Switzerland

Department of Genetics Assistance Publique des Hôpitaux de Paris Hôpital Pitié Salpêtrière F 75013 Paris France

Department of Genetics University Medical Center Utrecht Utrecht The Netherlands

Department of Medicine Divisions of Neurology and Respirology Queen's University Kingston Ontario Canada

Department of Neurology Academic Center for Epileptology Kempenhaeghe Heeze The Netherlands

Department of Neurology and Rehabilitation Tallinn Children's Hospital Tallinn Estonia

Department of Neurology centre de référence des épilepsies rares University Hospital of Strasbourg Strasbourg France

Department of Neurology F M Kirby Neurobiology Center Boston Children's Hospital Boston Massachusetts USA

Department of Neurology Harvard Medical School Boston Massachusetts USA

Department of Paediatric Neurology Motol University Hospital 2nd faculty of medicine Charles University Prague Czech Republic

Department of Pediatric Neurology and Developmental Medicine University Children's Hospital Tübingen Germany

Department of Pediatric Neurology Antwerp University Hospital Edegem Belgium

Department of Pediatric Neurology Children's Hospital Datteln Witten Herdecke University Datteln Germany

Department of Pediatric Neurology Rady Children's Hospital University of California San Diego California USA

Department of Pediatric Neurosurgery Fondation Rothschild F 75019 Paris France

Department of Pediatrics centre de référence des épilepsies rares University Hospital of Strasbourg Strasbourg France

Department of Pediatrics Institute of Medicine University Hospital of Udine Udine Italy

Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program Boston Children's Hospital Boston Massachusetts USA

Division of Genetics and Metabolism Phoenix Children's Hospital Phoenix Arizona USA

Epilepsy Center Clinic of Nervous System Diseases University of Foggia Riuniti Hospital Foggia Italy

Epilepsy Center for Children Brandenburg Medical School University Hospital Neuruppin Germany

IGBMC INSERM CNRS Strasbourg University Strasbourg France

INSERM U1127 F 75013 Paris France

Inserm UMR 1231 GAD Team Genetics of Developmental Anomalies et FHU TRANSLAD CHU Université de Bourgogne Franche Comté Dijon France

Institut de Systématique Evolution Biodiversité ISYEB UMR 7205 CNRS MNHN UPMC EPHE Paris France

Institut du Cerveau et de la Moelle épinière Hôpital Pitié Salpêtrière F 75013 Paris France

Institute of Human Genetics University Hospital Magdeburg Germany

Institute of Human Genetics University of Leipzig Hospitals and Clinics Leipzig Germany

Institute of Neurology Department of Medical and Surgical Sciences University Magna Græcia Catanzaro Italy

IRCCS Istituto delle Scienze Neurologiche of Bologna; Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy

Kinderneurologisches Zentrum Düsseldorf Gerresheim Sana Kliniken Düsseldorf Germany

Kingston Health Sciences Centre Kingston Ontario K7L 2V7 Canada

Leiden University Medical Center Leiden The Netherlands

Medical Genetics Unit Polyclinic Sant' Orsola Malpighi University Hospital Bologna Italy

Neurogenetics Group VIB Department of Molecular Genetics University of Antwerp Antwerp Belgium

Paediatric Clinical Epileptology Sleep disorders and Functional Neurology University Hospitals of Lyon Lyon France

Pediatric Neurology and Muscular Diseases Unit Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa G Gaslini Institute Genova Italy

Pediatric Neurology Department Timone Hospital APHM Marseille France

Pediatric Neurology Neurogenetics and Neurobiology Unit and Laboratories A Meyer Children's Hospital Florence Italy

Service d'Epileptologie Clinique CHU de Bordeaux France

Service de Génétique Hospices Civils de Lyon GHE; CNRS UMR 5292 INSERM U1028 CNRL et Université Claude Bernard Lyon 1 GHE Lyon France

Service de Génétique Médicale Pavillon Lefebvre Hôpital Purpan CHU Toulouse Toulouse France

Service de neurophysiologie et pédiatrie 1 CHU de Dijon Dijon France

Sorbonne Université UPMC Univ Paris 06 UMR S 1127 F 75013 Paris France

Stichting Epilepsie Instellingen Nederland Zwolle Heemstede The Netherlands

The Saxon Epilepsy Center Kleinwachau Radeberg Germany

Unit of Medical Genetics CHU La Réunion Saint Pierre F 97448 France

Unité d'épileptologie Service de Neurologie CHU 49033 Angers France

Vrije Universiteit Brussel Neurogenetics Research Group Laarbeeklaan 101 1090 Brussels Belgium

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Genet Med. 2019 Jul;21(7):1671. doi: 10.1038/s41436-018-0284-1. PubMed

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Genet Med. 2019 Aug;21(8):1896. doi: 10.1038/s41436-018-0325-9. PubMed

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