De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
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从头序列和拷贝数变体与图雷氏障碍障碍密切相关，并暗示细胞极性在发病机理中。
DOI：
10.1016/j.celrep.2018.08.082
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发表时间：
2018-09-25
期刊：
影响因子：
8.8
通讯作者：
State MW
中科院分区：
文献类型：
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作者：
Wang S;Mandell JD;Kumar Y;Sun N;Morris MT;Arbelaez J;Nasello C;Dong S;Duhn C;Zhao X;Yang Z;Padmanabhuni SS;Yu D;King RA;Dietrich A;Khalifa N;Dahl N;Huang AY;Neale BM;Coppola G;Mathews CA;Scharf JM;Tourette International Collaborative Genetics Study (TIC Genetics);Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE);Tourette Association of America International Consortium for Genetics (TAAICG);Fernandez TV;Buxbaum JD;De Rubeis S;Grice DE;Xing J;Heiman GA;Tischfield JA;Paschou P;Willsey AJ;State MW
我们之前通过 511 个三人组的全外显子组测序确定了从头破坏性序列变异对抽动秽语障碍 (TD) 的影响。在这里，我们对另外 291 个 TD 三重奏进行了排序，并分析了 802 个三重奏的组合集。我们观察到单发家族中新发破坏性变异的比例过高，但多发家族中却没有；我们确定了一个高度可信的 TD 风险基因 CELSR3（钙粘蛋白 EGF LAG 七通道 G 型受体 3）；我们发现 TD 患者中与细胞极性相关的基因突变较多，这表明病理生物学中有一个共同的途径；我们确认 TD 中的从头拷贝数变异存在统计学上显着的过量。最后，我们确定了 TD 和强迫症之间的从头序列变异以及 TD 和自闭症谱系障碍之间的从头拷贝数变异的显着重叠，这与共同的遗传风险一致。王等人。扩展了他们早期在 TD 领域的外显子组测序工作，添加了 291 个三重体，并进行了组合分析，表明从头变异在父母未受影响的个体中具有更大的风险，将从头结构变异确定为危险因素，将 CELSR3 确定为风险基因，并在发病机制中暗示细胞极性。
We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk. Wang et al. expand their earlier exome-sequencing work in TD, adding 291 trios and conducting combined analyses suggesting de novo variants carry more risk in individuals with unaffected parents, establishing de novo structural variants as risk factors, identifying CELSR3 as a risk gene, and implicating cell polarity in pathogenesis.
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影响因子：
14.8
作者：
通讯作者：
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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：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
4
作者：
Bel, Christophe;Oguievetskaia, Ksenia;Faivre-Sarrailh, Catherine
通讯作者：
Faivre-Sarrailh, Catherine
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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