De novo mutations in epileptic encephalopathies.
De novo mutations in epileptic encephalopathies.
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作者：
癫痫性脑病（EE）是一组破坏性的严重儿童癫痫疾病，其原因往往是未知的。在这里，我们报告了两个经典EE患者的新生突变筛查：婴儿痉挛（IS，n=149）和Lennox-Gastaut综合征（LGS，n=115）。我们对264名先证者及其父母的外显子组进行了测序，并确认了329个从头突变。可能性分析显示，在人类群体中对功能性遗传变异最不耐受的约4，000个基因中存在显著过量的从头突变（p=2.9 × 10−3）。其中，GABRB 3在4名患者中具有新生突变，ALG 13在2名患者中具有相同的新生突变;这两种基因都显示出明确的统计学证据。给定相关的位点特异性突变率，这些结果偶然发生的概率分别为p=4.1 × 10−10和p=7.8 × 10−12。该队列中具有新生突变的其他基因包括：CACNA 1A、CHD 2、FLNA、GABRA 1、GRIN 1、GRIN 2B、HDAC 4、HNRNPU、IQSEC 2、MTOR和NEDD 4L。最后，我们发现观察到的从头突变在特定的基因集中富集，包括由脆性X蛋白调控的基因（p<10−8），正如自闭症谱系障碍（ASD）所报道的那样。
Epileptic encephalopathies (EE) are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here, we report a screen for de novo mutations in patients with two classical EE: infantile spasms (IS, n=149) and Lennox-Gastaut Syndrome (LGS, n=115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ~4,000 genes that are the most intolerant to functional genetic variation in the human population (p=2.9 × 10−3). Among these are GABRB3 with de novo mutations in four patients and ALG13 with the same de novo mutation in two patients; both genes show clear statistical evidence of association. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are p=4.1 × 10−10 and p=7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include: CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HDAC4, HNRNPU, IQSEC2, MTOR, and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the Fragile X protein (p<10−8), as was reported for autism spectrum disorders (ASD).
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影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
影响因子：
64.8
作者：
Kong A;Frigge ML;Masson G;Besenbacher S;Sulem P;Magnusson G;Gudjonsson SA;Sigurdsson A;Jonasdottir A;Jonasdottir A;Wong WS;Sigurdsson G;Walters GB;Steinberg S;Helgason H;Thorleifsson G;Gudbjartsson DF;Helgason A;Magnusson OT;Thorsteinsdottir U;Stefansson K
通讯作者：
Stefansson K
影响因子：
64.5
作者：
Klassen T;Davis C;Goldman A;Burgess D;Chen T;Wheeler D;McPherson J;Bourquin T;Lewis L;Villasana D;Morgan M;Muzny D;Gibbs R;Noebels J
通讯作者：
Noebels J
影响因子：
9.8
作者：
Kalscheuer, VM;Tao, J;Gécz, J
通讯作者：
Gécz, J
影响因子：
64.8
作者：
Sanders, Stephan J.;Murtha, Michael T.;Gupta, Abha R.;Murdoch, John D.;Raubeson, Melanie J.;Willsey, A. Jeremy;Ercan-Sencicek, A. Gulhan;DiLullo, Nicholas M.;Parikshak, Neelroop N.;Stein, Jason L.;Walker, Michael F.;Ober, Gordon T.;Teran, Nicole A.;Song, Youeun;El-Fishawy, Paul;Murtha, Ryan C.;Choi, Murim;Overton, John D.;Bjornson, Robert D.;Carriero, Nicholas J.;Meyer, Kyle A.;Bilguvar, Kaya;Mane, Shrikant M.;Sestan, Nenad;Lifton, Richard P.;Guenel, Murat;Roeder, Kathryn;Geschwind, Daniel H.;Devlin, Bernie;State, Matthew W.
通讯作者：
State, Matthew W.