The landscape of epilepsy-related GATOR1 variants
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The landscape of epilepsy-related GATOR1 variants. / Baldassari, Sara; Picard, Fabienne; Verbeek, Nienke E; van Kempen, Marjan; Brilstra, Eva H; Lesca, Gaetan; Conti, Valerio; Guerrini, Renzo; Bisulli, Francesca; Licchetta, Laura; Pippucci, Tommaso; Tinuper, Paolo; Hirsch, Edouard; de Saint Martin, Anne; Chelly, Jamel; Rudolf, Gabrielle; Chipaux, Mathilde; Ferrand-Sorbets, Sarah; Dorfmüller, Georg; Sisodiya, Sanjay; Balestrini, Simona; Schoeler, Natasha; Hernandez-Hernandez, Laura; Krithika, S; Oegema, Renske; Hagebeuk, Eveline; Gunning, Boudewijn; Deckers, Charles; Berghuis, Bianca; Wegner, Ilse; Niks, Erik; Jansen, Floor E; Braun, Kees; de Jong, Daniëlle; Rubboli, Guido; Talvik, Inga; Sander, Valentin; Uldall, Peter; Jacquemont, Marie-Line; Nava, Caroline; Leguern, Eric; Julia, Sophie; Gambardella, Antonio; d'Orsi, Giuseppe; Crichiutti, Giovanni; Faivre, Laurence; Darmency, Veronique; Benova, Barbora; Krsek, Pavel; Biraben, Arnaud; Lebre, Anne-Sophie; Jennesson, Mélanie; Sattar, Shifteh; Marchal, Cécile; Nordli, Douglas R; Lindstrom, Kristin; Striano, Pasquale; Lomax, Lysa Boissé; Kiss, Courtney; Bartolomei, Fabrice; Lepine, Anne Fabienne; Schoonjans, An-Sofie; Stouffs, Katrien; Jansen, Anna; Panagiotakaki, Eleni; Ricard-Mousnier, Brigitte; Thevenon, Julien; de Bellescize, Julitta; Catenoix, Hélène; Dorn, Thomas; Zenker, Martin; Müller-Schlüter, Karen; Brandt, Christian; Krey, Ilona; Polster, Tilman; Wolff, Markus; Balci, Meral; Rostasy, Kevin; Achaz, Guillaume; Zacher, Pia; Becher, Thomas; Cloppenborg, Thomas; Yuskaitis, Christopher J; Weckhuysen, Sarah; Poduri, Annapurna; Lemke, Johannes R; Møller, Rikke S; Baulac, Stéphanie.
In: Genetics In Medicine, Vol. 21, No. 2, 02.2019, p. 398-408.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 234700907