Format

Send to

Choose Destination
Genet Med. 2019 Feb;21(2):398-408. doi: 10.1038/s41436-018-0060-2. Epub 2018 Aug 10.

The landscape of epilepsy-related GATOR1 variants.

Author information

1
Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.
2
INSERM, U1127, F-75013, Paris, France.
3
CNRS, UMR 7225, F-75013, Paris, France.
4
Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
5
Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, F-75013, Paris, France.
6
Department of Clinical Neurosciences, University Hospitals and Medical School of Geneva, Geneva, Switzerland.
7
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
8
Service de Génétique, Hospices Civils de Lyon - GHE; CNRS UMR 5292, INSERM U1028, CNRL, et Université Claude Bernard Lyon 1, GHE, Lyon, France.
9
Pediatric Neurology, Neurogenetics, and Neurobiology Unit and Laboratories, A. Meyer Children's Hospital, Florence, Italy.
10
IRCCS, Istituto delle Scienze Neurologiche of Bologna; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
11
Medical Genetics Unit, Polyclinic Sant' Orsola-Malpighi University Hospital, Bologna, Italy.
12
Department of Neurology-centre de référence des épilepsies rares, University Hospital of Strasbourg, Strasbourg, France.
13
Department of Pediatrics - centre de référence des épilepsies rares, University Hospital of Strasbourg, Strasbourg, France.
14
IGBMC, INSERM, CNRS, Strasbourg University, Strasbourg, France.
15
Department of Pediatric Neurosurgery, Fondation Rothschild, F-75019, Paris, France.
16
Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, WC1N 3BG, and Chalfont Centre for Epilepsy, Bucks, UK.
17
Stichting Epilepsie Instellingen Nederland, Zwolle/Heemstede, The Netherlands.
18
Leiden University Medical Center, Leiden, The Netherlands.
19
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.
20
Department of Neurology, Academic Center for Epileptology Kempenhaeghe, Heeze, The Netherlands.
21
Danish Epilepsy Centre, Dianalund, University of Copenhagen, Copenhagen, Denmark.
22
Department of Neurology and Rehabilitation, Tallinn Children's Hospital, Tallinn, Estonia.
23
Danish Epilepsy Centre, Dianalund, Denmark.
24
Unit of Medical Genetics, CHU La Réunion, Saint Pierre, F-97448, France.
25
Service de Génétique Médicale, Pavillon Lefebvre, Hôpital Purpan CHU Toulouse, Toulouse, France.
26
Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy.
27
Epilepsy Center, Clinic of Nervous System Diseases, University of Foggia, Riuniti Hospital, Foggia, Italy.
28
Department of Pediatrics, Institute of Medicine, University Hospital of Udine, Udine, Italy.
29
Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, CHU de Dijon et Université de Bourgogne, Dijon, France.
30
Service de neurophysiologie et pédiatrie 1, CHU de Dijon, Dijon, France.
31
Department of Paediatric Neurology, Motol University Hospital, 2nd faculty of medicine Charles University, Prague, Czech Republic.
32
Centre Hospitalier Universitaire de Rennes, F-35000, Rennes, France.
33
CHU Reims, Hôpital Maison Blanche, Pôle de Biologie, Service de Génétique, Reims, F-51092, France.
34
CHU Reims, American Memorial Hospital, Service de Pédiatrie, REIMS, F-51092, France.
35
Department of Pediatric Neurology, Rady Children's Hospital/University of California, San Diego, California, USA.
36
Service d'Epileptologie Clinique, CHU de Bordeaux, France.
37
Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
38
Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, USA.
39
Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, "G. Gaslini" Institute, Genova, Italy.
40
Department of Medicine, Divisions of Neurology and Respirology, Queen's University, Kingston, Ontario, Canada.
41
Kingston Health Sciences Centre, Kingston, Ontario, K7L 2V7, Canada.
42
Pediatric Neurology Department, Timone Hospital, APHM, Marseille, France.
43
Department of Pediatric Neurology, Antwerp University Hospital, Edegem, Belgium.
44
Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Neurogenetics Research Group, Laarbeeklaan 101, 1090, Brussels, Belgium.
45
Paediatric Clinical Epileptology, Sleep disorders and Functional Neurology, University Hospitals of Lyon (HCL), Lyon, France.
46
Unité d'épileptologie, Service de Neurologie, CHU, 49033, Angers, France.
47
Inserm UMR 1231 GAD Team, Genetics of Developmental Anomalies, et FHU-TRANSLAD, CHU/Université de Bourgogne-Franche Comté, Dijon, France.
48
Clinique Bernoise, Crans-, Montana, Switzerland.
49
Institute of Human Genetics, University Hospital, Magdeburg, Germany.
50
Epilepsy Center for Children, Brandenburg Medical School, University Hospital, Neuruppin, Germany.
51
Bethel Epilepsy Centre, Bielefeld, Germany.
52
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
53
Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, Germany.
54
Department of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln, Germany.
55
Institut de Systématique, Evolution, Biodiversité, ISYEB, UMR 7205 CNRS MNHN UPMC EPHE, Paris, France.
56
The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany.
57
Kinderneurologisches Zentrum, Düsseldorf-Gerresheim, Sana Kliniken, Düsseldorf, Germany.
58
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts, USA.
59
Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Boston Children's Hospital, Boston, Massachusetts, USA.
60
Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
61
Neurogenetics Group, VIB-Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
62
Danish Epilepsy Centre, Dianalund; Institute for Regional Health research, University of Southern Denmark, Odense, Denmark.
63
Sorbonne Université, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France. stephanie.baulac@upmc.fr.
64
INSERM, U1127, F-75013, Paris, France. stephanie.baulac@upmc.fr.
65
CNRS, UMR 7225, F-75013, Paris, France. stephanie.baulac@upmc.fr.
66
Institut du Cerveau et de la Moelle épinière (ICM), Hôpital Pitié-Salpêtrière, F-75013, Paris, France. stephanie.baulac@upmc.fr.
67
Department of Genetics, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, F-75013, Paris, France. stephanie.baulac@upmc.fr.

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.

KEYWORDS:

DEPDC5; Focal cortical dysplasia; Genetic focal epilepsy; SUDEP; mTORC1 pathway

PMID:
30093711
PMCID:
PMC6292495
[Available on 2019-08-01]
DOI:
10.1038/s41436-018-0060-2

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center