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DOI 10.1038/s41436-018-0060-2

Медицинская библиотека · Genetics in medicine : official journal of the American College of Medical Genetics · 2018

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

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Аннотация

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.

Для цитирования: 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. The landscape of epilepsy-related GATOR1 variants.. Genetics in medicine : official journal of the American College of Medical Genetics. 2018. DOI: 10.1038/s41436-018-0060-2.

Предметные рубрики MeSH

AdolescentBrugada SyndromeChildChild, PreschoolDNA Copy Number VariationsEpilepsyFemaleGTPase-Activating ProteinsGenetic Predisposition to DiseaseHumansINDEL MutationInfantInfant, NewbornLoss of Function MutationMaleMechanistic Target of Rapamycin Complex 1Multiprotein ComplexesPedigreeRepressor ProteinsSeizuresSignal TransductionTumor Suppressor Proteins
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