TY - JOUR

T1 - The landscape of epilepsy-related GATOR1 variants

AU - Baldassari, Sara

AU - Picard, Fabienne

AU - Verbeek, Nienke E

AU - van Kempen, Marjan

AU - Brilstra, Eva H

AU - Lesca, Gaetan

AU - Conti, Valerio

AU - Guerrini, Renzo

AU - Bisulli, Francesca

AU - Licchetta, Laura

AU - Pippucci, Tommaso

AU - Tinuper, Paolo

AU - Hirsch, Edouard

AU - de Saint Martin, Anne

AU - Chelly, Jamel

AU - Rudolf, Gabrielle

AU - Chipaux, Mathilde

AU - Ferrand-Sorbets, Sarah

AU - Dorfmüller, Georg

AU - Sisodiya, Sanjay

AU - Balestrini, Simona

AU - Schoeler, Natasha

AU - Hernandez-Hernandez, Laura

AU - Krithika, S

AU - Oegema, Renske

AU - Hagebeuk, Eveline

AU - Gunning, Boudewijn

AU - Deckers, Charles

AU - Berghuis, Bianca

AU - Wegner, Ilse

AU - Niks, Erik

AU - Jansen, Floor E

AU - Braun, Kees

AU - de Jong, Daniëlle

AU - Rubboli, Guido

AU - Talvik, Inga

AU - Sander, Valentin

AU - Uldall, Peter

AU - Jacquemont, Marie-Line

AU - Nava, Caroline

AU - Leguern, Eric

AU - Julia, Sophie

AU - Gambardella, Antonio

AU - d'Orsi, Giuseppe

AU - Crichiutti, Giovanni

AU - Faivre, Laurence

AU - Darmency, Veronique

AU - Benova, Barbora

AU - Krsek, Pavel

AU - Biraben, Arnaud

AU - Lebre, Anne-Sophie

AU - Jennesson, Mélanie

AU - Sattar, Shifteh

AU - Marchal, Cécile

AU - Nordli, Douglas R

AU - Lindstrom, Kristin

AU - Striano, Pasquale

AU - Lomax, Lysa Boissé

AU - Kiss, Courtney

AU - Bartolomei, Fabrice

AU - Lepine, Anne Fabienne

AU - Schoonjans, An-Sofie

AU - Stouffs, Katrien

AU - Jansen, Anna

AU - Panagiotakaki, Eleni

AU - Ricard-Mousnier, Brigitte

AU - Thevenon, Julien

AU - de Bellescize, Julitta

AU - Catenoix, Hélène

AU - Dorn, Thomas

AU - Zenker, Martin

AU - Müller-Schlüter, Karen

AU - Brandt, Christian

AU - Krey, Ilona

AU - Polster, Tilman

AU - Wolff, Markus

AU - Balci, Meral

AU - Rostasy, Kevin

AU - Achaz, Guillaume

AU - Zacher, Pia

AU - Becher, Thomas

AU - Cloppenborg, Thomas

AU - Yuskaitis, Christopher J

AU - Weckhuysen, Sarah

AU - Poduri, Annapurna

AU - Lemke, Johannes R

AU - Møller, Rikke S

AU - Baulac, Stéphanie

PY - 2019/2

Y1 - 2019/2

N2 - 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.

AB - 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.

KW - Adolescent

KW - Brugada Syndrome/genetics

KW - Child

KW - Child, Preschool

KW - DNA Copy Number Variations/genetics

KW - Epilepsy/complications

KW - Female

KW - GTPase-Activating Proteins/genetics

KW - Genetic Predisposition to Disease

KW - Humans

KW - INDEL Mutation/genetics

KW - Infant

KW - Infant, Newborn

KW - Loss of Function Mutation/genetics

KW - Male

KW - Mechanistic Target of Rapamycin Complex 1/genetics

KW - Multiprotein Complexes/genetics

KW - Pedigree

KW - Repressor Proteins/genetics

KW - Seizures/complications

KW - Signal Transduction/genetics

KW - Tumor Suppressor Proteins/genetics

U2 - 10.1038/s41436-018-0060-2

DO - 10.1038/s41436-018-0060-2

M3 - Journal article

C2 - 30093711

VL - 21

SP - 398

EP - 408

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 2

ER -