The landscape of epilepsy-related GATOR1 variants.
The landscape of epilepsy-related GATOR1 variants.
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DOI：
10.1038/s41436-018-0060-2
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Baulac S
中科院分区：
文献类型：
--
作者：
Baldassari S;Picard F;Verbeek NE;van Kempen M;Brilstra EH;Lesca G;Conti V;Guerrini R;Bisulli F;Licchetta L;Pippucci T;Tinuper P;Hirsch E;de Saint Martin A;Chelly J;Rudolf G;Chipaux M;Ferrand-Sorbets S;Dorfmüller G;Sisodiya S;Balestrini S;Schoeler N;Hernandez-Hernandez L;Krithika S;Oegema R;Hagebeuk E;Gunning B;Deckers C;Berghuis B;Wegner I;Niks E;Jansen FE;Braun K;de Jong D;Rubboli G;Talvik I;Sander V;Uldall P;Jacquemont ML;Nava C;Leguern E;Julia S;Gambardella A;d'Orsi G;Crichiutti G;Faivre L;Darmency V;Benova B;Krsek P;Biraben A;Lebre AS;Jennesson M;Sattar S;Marchal C;Nordli DR Jr;Lindstrom K;Striano P;Lomax LB;Kiss C;Bartolomei F;Lepine AF;Schoonjans AS;Stouffs K;Jansen A;Panagiotakaki E;Ricard-Mousnier B;Thevenon J;de Bellescize J;Catenoix H;Dorn T;Zenker M;Müller-Schlüter K;Brandt C;Krey I;Polster T;Wolff M;Balci M;Rostasy K;Achaz G;Zacher P;Becher T;Cloppenborg T;Yuskaitis CJ;Weckhuysen S;Poduri A;Lemke JR;Møller RS;Baulac S
为了确定与编码GATOR 1复合物（mTORC 1通路的负调节因子）的DEPDC5、NPRL 2和NPRL 3基因相关的癫痫的表型和突变谱，我们分析了73例在GATOR 1编码基因中具有癫痫相关变体的新先证者（家族性和散发性）的临床和遗传数据，并提出了GATOR 1变体临床解释的新指南。GATOR 1癫痫发作表型主要包括局灶性癫痫发作（例如，运动过度或额叶癫痫发作（50%），平均发病年龄为4.4岁，通常与睡眠相关且耐药（54%），并伴有局灶性皮质发育不良（20%）。据报道，10%的先证者有婴儿痉挛。癫痫猝死（SUDEP）发生在10%的家庭。所有140种癫痫相关GATOR 1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%是意义不确定的变体，3%可能是良性的。我们的数据强调了GATOR 1基因在局灶性癫痫发病机制中越来越重要的作用（迄今为止已有超过180例先证者）。GATOR 1表型谱的范围从伴有认知障碍共病的散发性早发性癫痫到家族性局灶性癫痫和SUDEP。
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 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. 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. 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.
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DOI：
10.1038/gim.2017.218
发表时间：
2018-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Kelly MA;Caleshu C;Morales A;Buchan J;Wolf Z;Harrison SM;Cook S;Dillon MW;Garcia J;Haverfield E;Jongbloed JDH;Macaya D;Manrai A;Orland K;Richard G;Spoonamore K;Thomas M;Thomson K;Vincent LM;Walsh R;Watkins H;Whiffin N;Ingles J;van Tintelen JP;Semsarian C;Ware JS;Hershberger R;Funke B
通讯作者：
Funke B
DOI：
10.1212/nxg.0000000000000028
发表时间：
2015-12
期刊：
Neurology. Genetics
影响因子：
--
作者：
Nascimento FA;Borlot F;Cossette P;Minassian BA;Andrade DM
通讯作者：
Andrade DM
DOI：
10.1212/nxg.0000000000000016
发表时间：
2015-08
期刊：
Neurology. Genetics
影响因子：
--
作者：
Carvill GL;Crompton DE;Regan BM;McMahon JM;Saykally J;Zemel M;Schneider AL;Dibbens L;Howell KB;Mandelstam S;Leventer RJ;Harvey AS;Mullen SA;Berkovic SF;Sullivan J;Scheffer IE;Mefford HC
通讯作者：
Mefford HC
影响因子：
2.2
作者：
Cooper, Monica S.;Mcintosh, Anne;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.
影响因子：
11.2
作者：
Lal, Dennis;Reinthaler, Eva M.;Neubauer, Bernd A.
通讯作者：
Neubauer, Bernd A.