The clustering of functionally related genes contributes to CNV-mediated disease.
The clustering of functionally related genes contributes to CNV-mediated disease.
复制标题
DOI：
10.1101/gr.184325.114
复制
发表时间：
2015-06
期刊：
影响因子：
7
通讯作者：
Webber C
中科院分区：
文献类型：
--
作者：
Andrews T;Honti F;Pfundt R;de Leeuw N;Hehir-Kwa J;Vulto-van Silfhout A;de Vries B;Webber C
单拷贝数变异体(CNV)可以破坏功能相关的基因簇。我们证明多个功能相关基因的同时中断是发育障碍患者新生CNV的一个常见和显著的特征(P=1×10−3)。使用三个不同的功能网络，我们从两个独立的发育障碍个体队列中意外地识别出新生CNV中大量与功能相关的基因。与明显健康的CNV相比，多个功能相关基因的存在是CNV致病性的重要预测因子，并且比较大CNV的已知疾病或单倍体不足基因的存在更好地预测CNV的致病性。在新生CNV中发现的功能相关基因属于整个基因组中发现的所有功能相关基因簇的70%。新生CNV较良性CNV更易影响功能簇，且影响程度更大(P=6×10−4)。此外，这样的功能相关基因簇具有表型信息性：不同的患者拥有影响同一功能相关基因簇的CNV，表现出比预期更相似的表型(P<；0.05)。单个CNV跨越多个功能相似的基因，对这些变异如何发挥致病作用有很大贡献。
Clusters of functionally related genes can be disrupted by a single copy number variant (CNV). We demonstrate that the simultaneous disruption of multiple functionally related genes is a frequent and significant characteristic of de novo CNVs in patients with developmental disorders (P = 1 × 10−3). Using three different functional networks, we identified unexpectedly large numbers of functionally related genes within de novo CNVs from two large independent cohorts of individuals with developmental disorders. The presence of multiple functionally related genes was a significant predictor of a CNV's pathogenicity when compared to CNVs from apparently healthy individuals and a better predictor than the presence of known disease or haploinsufficient genes for larger CNVs. The functionally related genes found in the de novo CNVs belonged to 70% of all clusters of functionally related genes found across the genome. De novo CNVs were more likely to affect functional clusters and affect them to a greater extent than benign CNVs (P = 6 × 10−4). Furthermore, such clusters of functionally related genes are phenotypically informative: Different patients possessing CNVs that affect the same cluster of functionally related genes exhibit more similar phenotypes than expected (P < 0.05). The spanning of multiple functionally similar genes by single CNVs contributes substantially to how these variants exert their pathogenic effects.
登录
查看更多内容
影响因子：
14.9
作者：
Heger A;Ponting CP
通讯作者：
Ponting CP
影响因子：
4.3
作者：
Doelken SC;Köhler S;Mungall CJ;Gkoutos GV;Ruef BJ;Smith C;Smedley D;Bauer S;Klopocki E;Schofield PN;Westerfield M;Robinson PN;Lewis SE
通讯作者：
Lewis SE
影响因子：
5.2
作者：
Hochstenbach, Ron;Poot, Martin;Cuppen, Edwin
通讯作者：
Cuppen, Edwin
影响因子：
4.5
作者：
Huang N;Lee I;Marcotte EM;Hurles ME
通讯作者：
Hurles ME
影响因子：
30.8
作者：
Cooper, Gregory M.;Coe, Bradley P.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.