Mosaic structural variation in children with developmental disorders.
Mosaic structural variation in children with developmental disorders.
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DOI：
10.1093/hmg/ddv033
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发表时间：
2015-05-15
影响因子：
3.5
通讯作者：
Deciphering Developmental Disorders Study
中科院分区：
文献类型：
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作者：
King DA;Jones WD;Crow YJ;Dominiczak AF;Foster NA;Gaunt TR;Harris J;Hellens SW;Homfray T;Innes J;Jones EA;Joss S;Kulkarni A;Mansour S;Morris AD;Parker MJ;Porteous DJ;Shihab HA;Smith BH;Tatton-Brown K;Tolmie JL;Trzaskowski M;Vasudevan PC;Wakeling E;Wright M;Plomin R;Timpson NJ;Hurles ME;Deciphering Developmental Disorders Study
描述发育障碍的遗传原因是一个积极研究的领域。嵌合结构异常（定义为拷贝数或杂合性事件丢失，数量较大且仅存在于细胞子集中）已在 0.2-1.0% 经临床基因检测确定的儿童中检测到。然而，社区中健康儿童的频率尚未得到很好的表征，如果知道的话，可以更好地解释这种突变类别在患有发育障碍的儿童中的致病负担。在病例对照分析中，我们使用我们开发的分析流程比较了 1303 名患有发育障碍的儿童和 5094 名没有发育障碍的儿童之间的大规模嵌合率，并确定了病例的显着富集（比值比 = 39.4，P 值 1.073e − 6）。一项荟萃分析包括对另外 7000 名先天性疾病儿童的频率估计，产生了更强的统计丰富性（P 值 1.784e - 11）。此外，为了最大限度地检测先证者中的低克隆性事件，我们应用了基于三重奏的嵌合检测算法，该算法检测了先证者中的两个额外事件，包括具有全基因组疑似嵌合性的个体。我们总共在 1303 名儿童 (0.9%) 中检测到 12 种结构镶嵌异常。考虑到病例中检测到的嵌合现象的负担，我们怀疑先证者中检测到的许多事件都是致病性的。对每个检测到的变异的基因型-表型关系的审查评估表明，大多数事件很可能是致病的。这项工作量化了结构嵌合体作为发育障碍原因的负担。
Delineating the genetic causes of developmental disorders is an area of active investigation. Mosaic structural abnormalities, defined as copy number or loss of heterozygosity events that are large and present in only a subset of cells, have been detected in 0.2–1.0% of children ascertained for clinical genetic testing. However, the frequency among healthy children in the community is not well characterized, which, if known, could inform better interpretation of the pathogenic burden of this mutational category in children with developmental disorders. In a case–control analysis, we compared the rate of large-scale mosaicism between 1303 children with developmental disorders and 5094 children lacking developmental disorders, using an analytical pipeline we developed, and identified a substantial enrichment in cases (odds ratio = 39.4, P-value 1.073e − 6). A meta-analysis that included frequency estimates among an additional 7000 children with congenital diseases yielded an even stronger statistical enrichment (P-value 1.784e − 11). In addition, to maximize the detection of low-clonality events in probands, we applied a trio-based mosaic detection algorithm, which detected two additional events in probands, including an individual with genome-wide suspected chimerism. In total, we detected 12 structural mosaic abnormalities among 1303 children (0.9%). Given the burden of mosaicism detected in cases, we suspected that many of the events detected in probands were pathogenic. Scrutiny of the genotypic–phenotypic relationship of each detected variant assessed that the majority of events are very likely pathogenic. This work quantifies the burden of structural mosaicism as a cause of developmental disorders.
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影响因子：
30.8
作者：
Laurie, Cathy C.;Laurie, Cecelia A.;Rice, Kenneth;Doheny, Kimberly F.;Zelnick, Leila R.;McHugh, Caitlin P.;Ling, Hua;Hetrick, Kurt N.;Pugh, Elizabeth W.;Amos, Chris;Wei, Qingyi;Wang, Li-E;Lee, Jeffrey E.;Barnes, Kathleen C.;Hansel, Nadia N.;Mathias, Rasika;Daley, Denise;Beaty, Terri H.;Scott, Alan F.;Ruczinski, Ingo;Scharpf, Rob B.;Bierut, Laura J.;Hartz, Sarah M.;Landi, Maria Teresa;Freedman, Neal D.;Goldin, Lynn R.;Ginsburg, David;Li, Jun;Desch, Karl C.;Strom, Sara S.;Blot, William J.;Signorello, Lisa B.;Ingles, Sue A.;Chanock, Stephen J.;Berndt, Sonja I.;Le Marchand, Loic;Henderson, Brian E.;Monroe, Kristine R.;Heit, John A.;de Andrade, Mariza;Armasu, Sebastian M.;Regnier, Cynthia;Lowe, William L.;Hayes, M. Geoffrey;Marazita, Mary L.;Feingold, Eleanor;Murray, Jeffrey C.;Melbye, Mads;Feenstra, Bjarke;Kang, Jae H.;Wiggs, Janey L.;Jarvik, Gail P.;McDavid, Andrew N.;Seshan, Venkatraman E.;Mirel, Daniel B.;Crenshaw, Andrew;Sharopova, Nataliya;Wise, Anastasia;Shen, Jess;Crosslin, David R.;Levine, David M.;Zheng, Xiuwen;Udren, Jenna I.;Bennett, Siiri;Nelson, Sarah C.;Gogarten, Stephanie M.;Conomos, Matthew P.;Heagerty, Patrick;Manolio, Teri;Pasquale, Louis R.;Haiman, Christopher A.;Caporaso, Neil;Weir, Bruce S.
通讯作者：
Weir, Bruce S.
影响因子：
3.7
作者：
Behjati S;Maschietto M;Williams RD;Side L;Hubank M;West R;Pearson K;Sebire N;Tarpey P;Futreal A;Brooks T;Stratton MR;Anderson J
通讯作者：
Anderson J
影响因子：
4
作者：
Bruno, D. L.;White, S. M.;Slater, H. R.
通讯作者：
Slater, H. R.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Jacobs, Kevin B.;Yeager, Meredith;Zhou, Weiyin;Wacholder, Sholom;Wang, Zhaoming;Rodriguez-Santiago, Benjamin;Hutchinson, Amy;Deng, Xiang;Liu, Chenwei;Horner, Marie-Josephe;Cullen, Michael;Epstein, Caroline G.;Burdett, Laurie;Dean, Michael C.;Chatterjee, Nilanjan;Sampson, Joshua;Chung, Charles C.;Kovaks, Joseph;Gapstur, Susan M.;Stevens, Victoria L.;Teras, Lauren T.;Gaudet, Mia M.;Albanes, Demetrius;Weinstein, Stephanie J.;Virtamo, Jarmo;Taylor, Philip R.;Freedman, Neal D.;Abnet, Christian C.;Goldstein, Alisa M.;Hu, Nan;Yu, Kai;Yuan, Jian-Min;Liao, Linda;Ding, Ti;Qiao, You-Lin;Gao, Yu-Tang;Koh, Woon-Puay;Xiang, Yong-Bing;Tang, Ze-Zhong;Fan, Jin-Hu;Aldrich, Melinda C.;Amos, Christopher;Blot, William J.;Bock, Cathryn H.;Gillanders, Elizabeth M.;Harris, Curtis C.;Haiman, Christopher A.;Henderson, Brian E.;Kolonel, Laurence N.;Le Marchand, Loic;McNeill, Lorna H.;Rybicki, Benjamin A.;Schwartz, Ann G.;Signorello, Lisa B.;Spitz, Margaret R.;Wiencke, John K.;Wrensch, Margaret;Wu, Xifeng;Zanetti, Krista A.;Ziegler, Regina G.;Figueroa, Jonine D.;Garcia-Closas, Montserrat;Malats, Nuria;Marenne, Gaelle;Prokunina-Olsson, Ludmila;Baris, Dalsu;Schwenn, Molly;Johnson, Alison;Landi, Maria Teresa;Goldin, Lynn;Consonni, Dario;Bertazzi, Pier Alberto;Rotunno, Melissa;Rajaraman, Preetha;Andersson, Ulrika;Freeman, Laura E. Beane;Berg, Christine D.;Buring, Julie E.;Butler, Mary A.;Carreon, Tania;Feychting, Maria;Ahlbom, Anders;Gaziano, J. Michael;Giles, Graham G.;Hallmans, Goran;Hankinson, Susan E.;Hartge, Patricia;Henriksson, Roger;Inskip, Peter D.;Johansen, Christoffer;Landgren, Annelie;McKean-Cowdin, Roberta;Michaud, Dominique S.;Melin, Beatrice S.;Peters, Ulrike;Ruder, Avima M.;Sesso, Howard D.;Severi, Gianluca;Shu, Xiao-Ou;Visvanathan, Kala;White, Emily;Wolk, Alicja;Zeleniuch-Jacquotte, Anne;Zheng, Wei;Silverman, Debra T.;Kogevinas, Manolis;Gonzalez, Juan R.;Villa, Olaya;Li, Donghui;Duell, Eric J.;Risch, Harvey A.;Olson, Sara H.;Kooperberg, Charles;Wolpin, Brian M.;Jiao, Li;Hassan, Manal;Wheeler, William;Arslan, Alan A.;Bueno-de-Mesquita, H. Bas;Fuchs, Charles S.;Gallinger, Steven;Gross, Myron D.;Holly, Elizabeth A.;Klein, Alison P.;LaCroix, Andrea;Mandelson, Margaret T.;Petersen, Gloria;Boutron-Ruault, Marie-Christine;Bracci, Paige M.;Canzian, Federico;Chang, Kenneth;Cotterchio, Michelle;Giovannucci, Edward L.;Goggins, Michael;Bolton, Judith A. Hoffman;Jenab, Mazda;Khaw, Kay-Tee;Krogh, Vittorio;Kurtz, Robert C.;McWilliams, Robert R.;Mendelsohn, Julie B.;Rabe, Kari G.;Riboli, Elio;Tjonneland, Anne;Tobias, Geoffrey S.;Trichopoulos, Dimitrios;Elena, Joanne W.;Yu, Herbert;Amundadottir, Laufey;Stolzenberg-Solomon, Rachael Z.;Kraft, Peter;Schumacher, Fredrick;Stram, Daniel;Savage, Sharon A.;Mirabello, Lisa;Andrulis, Irene L.;Wunder, Jay S.;Patino Garcia, Ana;Sierrasesumaga, Luis;Barkauskas, Donald A.;Gorlick, Richard G.;Purdue, Mark;Chow, Wong-Ho;Moore, Lee E.;Schwartz, Kendra L.;Davis, Faith G.;Hsing, Ann W.;Berndt, Sonja I.;Black, Amanda;Wentzensen, Nicolas;Brinton, Louise A.;Lissowska, Jolanta;Peplonska, Beata;McGlynn, Katherine A.;Cook, Michael B.;Graubard, Barry I.;Kratz, Christian P.;Greene, Mark H.;Erickson, Ralph L.;Hunter, David J.;Thomas, Gilles;Hoover, Robert N.;Real, Francisco X.;Fraumeni, Joseph F., Jr.;Caporaso, Neil E.;Tucker, Margaret;Rothman, Nathaniel;Perez-Jurado, Luis A.;Chanock, Stephen J.
通讯作者：
Chanock, Stephen J.