6533b824fe1ef96bd1280168
RESEARCH PRODUCT
The landscape of epilepsy-related GATOR1 variants
Johannes R. LemkePia ZacherThomas DornLaura Hernandez-hernandezNatasha E. SchoelerStéphanie BaulacSara BaldassariAnne De Saint MartinEleni PanagiotakakiAnne Fabienne LepineMarkus WolffArnaud BirabenRenske OegemaEdouard HirschAnna JansenCharles DeckersNienke E. VerbeekFabienne PicardGeorg DorfmüllerSarah Ferrand-sorbetsBarbora BenovaFrancesca BisulliInga TalvikKristin LindstromTilman PolsterDouglas R. NordliTommaso PippucciEva H. BrilstraShifteh SattarErik H. NiksMarie Line JacquemontKees P.j. BraunKaren Müller-schlüterSanjay M. SisodiyaSarah WeckhuysenLysa Boissé LomaxSophie JuliaBrigitte Ricard-mousnierMathilde ChipauxLaura LicchettaGaetan LescaBianca BerghuisS. KrithikaJamel ChellyRenzo GuerriniHélène CatenoixAnnapurna PoduriAnnapurna PoduriMelanie JennessonPasquale StrianoRikke Rs MøllerAntonio GambardellaGuillaume AchazPeter UldallFabrice BartolomeiGiuseppe D'orsiLaurence FaivreFloor E. JansenAn Sofie SchoonjansKevin RostasyThomas BecherPavel KrsekJulien ThevenonMarjan J. A. Van KempenGuido RubboliCécile MarchalMeral BalciBoudewijn GunningIlona KreyJulitta De BellescizeVeronique DarmencyChristopher J. YuskaitisChristopher J. YuskaitisDaniëlle De JongGiovanni CrichiuttiPaolo TinuperKatrien StouffsValentin SanderAnne-sophie LebreThomas CloppenborgValerio ContiGabrielle RudolfCourtney KissEveline HagebeukCaroline NavaEric LeguernIlse WegnerChristian BrandtMartin ZenkerSimona Balestrinisubject
Male0301 basic medicineProbandDEPDC5SUDEP030105 genetics & heredityBioinformaticsLoss of Function Mutation/geneticsEpilepsyINDEL MutationLoss of Function MutationmTORC1 pathwayGenetics(clinical)ChildGenetics (clinical)Multiprotein Complexes/geneticsBrugada SyndromeDNA Copy Number VariationBrugada syndromeINDEL Mutation/geneticsGTPase-Activating ProteinsNPRL3SeizureDEPDC5PhenotypePedigree3. Good healthBrugada Syndrome/geneticsChild PreschoolFemaleHumanSignal TransductionDNA Copy Number VariationsAdolescentSeizures/complicationsMechanistic Target of Rapamycin Complex 1/geneticsDNA Copy Number Variations/geneticsMechanistic Target of Rapamycin Complex 1Tumor Suppressor Proteins/geneticsArticleFocal cortical dysplasia03 medical and health sciencesSeizuresGTPase-Activating Proteins/geneticsmedicineHumansGenetic Predisposition to DiseaseDEPDC5; Focal cortical dysplasia; Genetic focal epilepsy; mTORC1 pathway; SUDEPGenetic focal epilepsyEpilepsy/complicationsRepressor Proteins/geneticsEpilepsybusiness.industryGTPase-Activating ProteinTumor Suppressor ProteinsInfant NewbornCorrectionInfantRepressor ProteinCortical dysplasiamedicine.diseaseddc:616.8Repressor Proteins030104 developmental biologyFrontal lobe seizures[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human geneticsMultiprotein ComplexesMultiprotein ComplexeSignal Transduction/geneticsHuman medicinebusinessdescription
Purpose:\ud \ud 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.\ud \ud Methods:\ud \ud 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.\ud \ud Results:\ud \ud 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.\ud \ud Conclusion:\ud \ud 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-02-01 |