No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.
No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.
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DOI：
10.1371/journal.pgen.1004852
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发表时间：
2015-01
期刊：
影响因子：
4.5
通讯作者：
State MW
中科院分区：
文献类型：
--
作者：
Murdoch JD;Gupta AR;Sanders SJ;Walker MF;Keaney J;Fernandez TV;Murtha MT;Anyanwu S;Ober GT;Raubeson MJ;DiLullo NM;Villa N;Waqar Z;Sullivan C;Gonzalez L;Willsey AJ;Choe SY;Neale BM;Daly MJ;State MW
接触蛋白和接触蛋白相关蛋白，特别是接触蛋白相关蛋白样2（CNTNAP 2），已被广泛引用为自闭症风险基因的基础上，从纯合性作图，分子细胞遗传学，拷贝数变异分析的结果，以及常见和罕见的单核苷酸协会的研究。然而，具体关于杂合单核苷酸变异（SNV）的贡献的数据一直不一致。为了阐明CNTNAP 2和相关基因家族中罕见点突变的作用，我们进行了有针对性的下一代测序，并在总计2704例病例和2747例对照的队列中评估了现有序列数据。我们没有发现任何CNTN或CNTNAP基因（包括CNTNAP 2）中的罕见杂合突变具有统计学显著相关性的证据，这对它们对风险的合理贡献的规模有明显的限制。自闭症谱系障碍（ASD）的先前遗传研究已经证明了接触蛋白相关蛋白样2蛋白（CNTNAP 2）以及编码接触蛋白和接触蛋白相关蛋白的其他基因的作用。虽然有强有力的证据表明，CNTNAP 2基因的两个拷贝的丢失会导致自闭症和癫痫，但该基因的一个拷贝或相关基因的一个拷贝的突变的影响尚不清楚。我们对1000多名自闭症患者和近1000名未受影响的对照组进行了大规模DNA测序，在寻找被预测会破坏蛋白质功能的罕见突变时，没有发现接触蛋白家族中的6个基因和接触蛋白相关蛋白家族中的4个基因中的任何一个有显著关联，并且只存在于相应基因的一个拷贝中。然后，我们将来自我们实验室的CNTNAP 2数据与来自另一个研究实验室的CNTNAP 2数据相结合，发现该基因的有害杂合突变没有显着关联。考虑到在合并样本中鉴定的无义突变很少，对其影响的评估受到限制。然而，CNTNAP 2和其他接触蛋白或接触蛋白相关蛋白的错义杂合突变在受影响的个体中与对照组相比没有升高，因此，作为一个群体，对自闭症谱系障碍的风险没有显著影响。
Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk. Prior genetic studies of autism spectrum disorders (ASD) have demonstrated a role for Contactin-Associated Protein-Like 2 protein (CNTNAP2), as well as for other genes that code for Contactin proteins and Contactin-Associated Proteins. While there is strong evidence that the loss of two copies of the gene CNTNAP2 causes autism and epilepsy, the impact of mutations in only one copy of this gene, or in only one copy of related genes, is less clear. We performed large-scale DNA sequencing on a cohort of over 1000 autism patients and nearly 1000 unaffected controls and did not find significant association at any of 6 genes in the Contactin family and 4 genes in the Contactin-Associated Protein family when looking for rare mutations that are predicted to be disruptive to the protein’s function and are present in only one copy of the respective gene. We then combined the data on CNTNAP2 from our laboratory with CNTNAP2 data from another research laboratory, and found no significant association of deleterious heterozygous mutations at this gene. Given the paucity of nonsense mutations identified across the combined sample, an assessment of their impact was circumscribed. However, missense heterozygous mutations in CNTNAP2 and in other Contactins or Contactin-Associated Proteins are not elevated in affected individuals versus controls and, consequently, do not have a marked impact, as a group, on the risk for autism spectrum disorders.
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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：
4.5
作者：
Liu L;Sabo A;Neale BM;Nagaswamy U;Stevens C;Lim E;Bodea CA;Muzny D;Reid JG;Banks E;Coon H;Depristo M;Dinh H;Fennel T;Flannick J;Gabriel S;Garimella K;Gross S;Hawes A;Lewis L;Makarov V;Maguire J;Newsham I;Poplin R;Ripke S;Shakir K;Samocha KE;Wu Y;Boerwinkle E;Buxbaum JD;Cook EH Jr;Devlin B;Schellenberg GD;Sutcliffe JS;Daly MJ;Gibbs RA;Roeder K
通讯作者：
Roeder K
影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
4.5
作者：
Chahrour MH;Yu TW;Lim ET;Ataman B;Coulter ME;Hill RS;Stevens CR;Schubert CR;ARRA Autism Sequencing Collaboration;Greenberg ME;Gabriel SB;Walsh CA
通讯作者：
Walsh CA
影响因子：
3.5
作者：
Anney R;Klei L;Pinto D;Almeida J;Bacchelli E;Baird G;Bolshakova N;Bölte S;Bolton PF;Bourgeron T;Brennan S;Brian J;Casey J;Conroy J;Correia C;Corsello C;Crawford EL;de Jonge M;Delorme R;Duketis E;Duque F;Estes A;Farrar P;Fernandez BA;Folstein SE;Fombonne E;Gilbert J;Gillberg C;Glessner JT;Green A;Green J;Guter SJ;Heron EA;Holt R;Howe JL;Hughes G;Hus V;Igliozzi R;Jacob S;Kenny GP;Kim C;Kolevzon A;Kustanovich V;Lajonchere CM;Lamb JA;Law-Smith M;Leboyer M;Le Couteur A;Leventhal BL;Liu XQ;Lombard F;Lord C;Lotspeich L;Lund SC;Magalhaes TR;Mantoulan C;McDougle CJ;Melhem NM;Merikangas A;Minshew NJ;Mirza GK;Munson J;Noakes C;Nygren G;Papanikolaou K;Pagnamenta AT;Parrini B;Paton T;Pickles A;Posey DJ;Poustka F;Ragoussis J;Regan R;Roberts W;Roeder K;Roge B;Rutter ML;Schlitt S;Shah N;Sheffield VC;Soorya L;Sousa I;Stoppioni V;Sykes N;Tancredi R;Thompson AP;Thomson S;Tryfon A;Tsiantis J;Van Engeland H;Vincent JB;Volkmar F;Vorstman JA;Wallace S;Wing K;Wittemeyer K;Wood S;Zurawiecki D;Zwaigenbaum L;Bailey AJ;Battaglia A;Cantor RM;Coon H;Cuccaro ML;Dawson G;Ennis S;Freitag CM;Geschwind DH;Haines JL;Klauck SM;McMahon WM;Maestrini E;Miller J;Monaco AP;Nelson SF;Nurnberger JI Jr;Oliveira G;Parr JR;Pericak-Vance MA;Piven J;Schellenberg GD;Scherer SW;Vicente AM;Wassink TH;Wijsman EM;Betancur C;Buxbaum JD;Cook EH;Gallagher L;Gill M;Hallmayer J;Paterson AD;Sutcliffe JS;Szatmari P;Vieland VJ;Hakonarson H;Devlin B
通讯作者：
Devlin B