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The landscape of epilepsy-related GATOR1 variants.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2018-08-10 , DOI: 10.1038/s41436-018-0060-2 Sara Baldassari 1, 2, 3, 4, 5 , Fabienne Picard 6 , Nienke E Verbeek 7 , Marjan van Kempen 7 , Eva H Brilstra 7 , Gaetan Lesca 8 , Valerio Conti 9 , Renzo Guerrini 9 , Francesca Bisulli 10 , Laura Licchetta 10 , Tommaso Pippucci 11 , Paolo Tinuper 10 , Edouard Hirsch 12 , Anne de Saint Martin 13 , Jamel Chelly 14 , Gabrielle Rudolf 14 , Mathilde Chipaux 15 , Sarah Ferrand-Sorbets 15 , Georg Dorfmüller 15 , Sanjay Sisodiya 16 , Simona Balestrini 16 , Natasha Schoeler 16 , Laura Hernandez-Hernandez 16 , S Krithika 16 , Renske Oegema 7 , Eveline Hagebeuk 17 , Boudewijn Gunning 17 , Charles Deckers 17 , Bianca Berghuis 17 , Ilse Wegner 17 , Erik Niks 18 , Floor E Jansen 19 , Kees Braun 19 , Daniëlle de Jong 20 , Guido Rubboli 21 , Inga Talvik 22 , Valentin Sander 22 , Peter Uldall 23 , Marie-Line Jacquemont 24 , Caroline Nava 1, 2, 3, 4, 5 , Eric Leguern 1, 2, 3, 4, 5 , Sophie Julia 25 , Antonio Gambardella 26 , Giuseppe d'Orsi 27 , Giovanni Crichiutti 28 , Laurence Faivre 29 , Veronique Darmency 30 , Barbora Benova 31 , Pavel Krsek 31 , Arnaud Biraben 32 , Anne-Sophie Lebre 33 , Mélanie Jennesson 34 , Shifteh Sattar 35 , Cécile Marchal 36 , Douglas R Nordli 37 , Kristin Lindstrom 38 , Pasquale Striano 39 , Lysa Boissé Lomax 40, 41 , Courtney Kiss 41 , Fabrice Bartolomei 42 , Anne Fabienne Lepine 42 , An-Sofie Schoonjans 43 , Katrien Stouffs 44 , Anna Jansen 44 , Eleni Panagiotakaki 45 , Brigitte Ricard-Mousnier 46 , Julien Thevenon 47 , Julitta de Bellescize 45 , Hélène Catenoix 45 , Thomas Dorn 48 , Martin Zenker 49 , Karen Müller-Schlüter 50 , Christian Brandt 51 , Ilona Krey 52 , Tilman Polster 51 , Markus Wolff 53 , Meral Balci 54 , Kevin Rostasy 54 , Guillaume Achaz 55 , Pia Zacher 56 , Thomas Becher 57 , Thomas Cloppenborg 51 , Christopher J Yuskaitis 58, 59, 60 , Sarah Weckhuysen 61 , Annapurna Poduri 58, 59, 60 , Johannes R Lemke 52 , Rikke S Møller 62 , Stéphanie Baulac 1, 2, 3, 4, 5
Genetics in Medicine ( IF 6.6 ) Pub Date : 2018-08-10 , DOI: 10.1038/s41436-018-0060-2 Sara Baldassari 1, 2, 3, 4, 5 , Fabienne Picard 6 , Nienke E Verbeek 7 , Marjan van Kempen 7 , Eva H Brilstra 7 , Gaetan Lesca 8 , Valerio Conti 9 , Renzo Guerrini 9 , Francesca Bisulli 10 , Laura Licchetta 10 , Tommaso Pippucci 11 , Paolo Tinuper 10 , Edouard Hirsch 12 , Anne de Saint Martin 13 , Jamel Chelly 14 , Gabrielle Rudolf 14 , Mathilde Chipaux 15 , Sarah Ferrand-Sorbets 15 , Georg Dorfmüller 15 , Sanjay Sisodiya 16 , Simona Balestrini 16 , Natasha Schoeler 16 , Laura Hernandez-Hernandez 16 , S Krithika 16 , Renske Oegema 7 , Eveline Hagebeuk 17 , Boudewijn Gunning 17 , Charles Deckers 17 , Bianca Berghuis 17 , Ilse Wegner 17 , Erik Niks 18 , Floor E Jansen 19 , Kees Braun 19 , Daniëlle de Jong 20 , Guido Rubboli 21 , Inga Talvik 22 , Valentin Sander 22 , Peter Uldall 23 , Marie-Line Jacquemont 24 , Caroline Nava 1, 2, 3, 4, 5 , Eric Leguern 1, 2, 3, 4, 5 , Sophie Julia 25 , Antonio Gambardella 26 , Giuseppe d'Orsi 27 , Giovanni Crichiutti 28 , Laurence Faivre 29 , Veronique Darmency 30 , Barbora Benova 31 , Pavel Krsek 31 , Arnaud Biraben 32 , Anne-Sophie Lebre 33 , Mélanie Jennesson 34 , Shifteh Sattar 35 , Cécile Marchal 36 , Douglas R Nordli 37 , Kristin Lindstrom 38 , Pasquale Striano 39 , Lysa Boissé Lomax 40, 41 , Courtney Kiss 41 , Fabrice Bartolomei 42 , Anne Fabienne Lepine 42 , An-Sofie Schoonjans 43 , Katrien Stouffs 44 , Anna Jansen 44 , Eleni Panagiotakaki 45 , Brigitte Ricard-Mousnier 46 , Julien Thevenon 47 , Julitta de Bellescize 45 , Hélène Catenoix 45 , Thomas Dorn 48 , Martin Zenker 49 , Karen Müller-Schlüter 50 , Christian Brandt 51 , Ilona Krey 52 , Tilman Polster 51 , Markus Wolff 53 , Meral Balci 54 , Kevin Rostasy 54 , Guillaume Achaz 55 , Pia Zacher 56 , Thomas Becher 57 , Thomas Cloppenborg 51 , Christopher J Yuskaitis 58, 59, 60 , Sarah Weckhuysen 61 , Annapurna Poduri 58, 59, 60 , Johannes R Lemke 52 , Rikke S Møller 62 , Stéphanie Baulac 1, 2, 3, 4, 5
Affiliation
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.
中文翻译：
癫痫相关 GATOR1 变体的景观。
目的 确定与编码 GATOR1 复合体（mTORC1 通路的负调节因子）相关的 DEPDC5、NPRL2 和 NPRL3 基因的表型和突变谱GATOR1 编码基因中的相关变体，并提出了 GATOR1 变体临床解释的新指南。结果 GATOR1 癫痫发作表型主要包括局灶性癫痫发作（例如，50% 的过度运动或额叶癫痫发作），平均发病年龄为 4.4 岁，通常与睡眠相关和耐药性 (54%)，并与局灶性癫痫发作相关。皮质发育不良（20%）。10% 的先证者报告了婴儿痉挛。10% 的家庭发生癫痫猝死（SUDEP）。所有 140 种癫痫相关 GATOR1 变体（包括本研究的变体）的新分类框架显示，68% 是功能丧失致病性，14% 可能是致病性，15% 是不确定意义的变体，3% 可能是良性的. 结论 我们的数据强调了 GATOR1 基因在局灶性癫痫发病机制中的日益重要的作用（迄今为止已有超过 180 名先证者）。GATOR1 表型谱范围从伴有认知障碍合并症的散发性早发性癫痫到家族性局灶性癫痫和 SUDEP。结论 我们的数据强调了 GATOR1 基因在局灶性癫痫发病机制中的日益重要的作用（迄今为止已有超过 180 名先证者）。GATOR1 表型谱范围从伴有认知障碍合并症的散发性早发性癫痫到家族性局灶性癫痫和 SUDEP。结论 我们的数据强调了 GATOR1 基因在局灶性癫痫发病机制中的日益重要的作用（迄今为止已有超过 180 名先证者）。GATOR1 表型谱范围从伴有认知障碍合并症的散发性早发性癫痫到家族性局灶性癫痫和 SUDEP。
更新日期：2018-08-10
中文翻译：
癫痫相关 GATOR1 变体的景观。
目的 确定与编码 GATOR1 复合体（mTORC1 通路的负调节因子）相关的 DEPDC5、NPRL2 和 NPRL3 基因的表型和突变谱GATOR1 编码基因中的相关变体，并提出了 GATOR1 变体临床解释的新指南。结果 GATOR1 癫痫发作表型主要包括局灶性癫痫发作（例如，50% 的过度运动或额叶癫痫发作），平均发病年龄为 4.4 岁，通常与睡眠相关和耐药性 (54%)，并与局灶性癫痫发作相关。皮质发育不良（20%）。10% 的先证者报告了婴儿痉挛。10% 的家庭发生癫痫猝死（SUDEP）。所有 140 种癫痫相关 GATOR1 变体（包括本研究的变体）的新分类框架显示，68% 是功能丧失致病性，14% 可能是致病性，15% 是不确定意义的变体，3% 可能是良性的. 结论 我们的数据强调了 GATOR1 基因在局灶性癫痫发病机制中的日益重要的作用（迄今为止已有超过 180 名先证者）。GATOR1 表型谱范围从伴有认知障碍合并症的散发性早发性癫痫到家族性局灶性癫痫和 SUDEP。结论 我们的数据强调了 GATOR1 基因在局灶性癫痫发病机制中的日益重要的作用（迄今为止已有超过 180 名先证者）。GATOR1 表型谱范围从伴有认知障碍合并症的散发性早发性癫痫到家族性局灶性癫痫和 SUDEP。结论 我们的数据强调了 GATOR1 基因在局灶性癫痫发病机制中的日益重要的作用（迄今为止已有超过 180 名先证者）。GATOR1 表型谱范围从伴有认知障碍合并症的散发性早发性癫痫到家族性局灶性癫痫和 SUDEP。
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