Andrews Tallulah, Honti Frantisek, Pfundt Rolph, de Leeuw Nicole, Hehir-Kwa Jayne, Vulto-van Silfhout Anneke, de Vries Bert, Webber Caleb
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom;
Department of Human Genetics and the Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
Genome Res. 2015 Jun;25(6):802-13. doi: 10.1101/gr.184325.114. Epub 2015 Apr 17.
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.
功能相关基因簇可能会被单个拷贝数变异（CNV）破坏。我们证明，多个功能相关基因的同时破坏是发育障碍患者新生CNV的一个常见且显著的特征（P = 1×10⁻³）。使用三种不同的功能网络，我们在两个大型独立的发育障碍个体队列的新生CNV中意外地发现了大量功能相关基因。与明显健康个体的CNV相比，多个功能相关基因的存在是CNV致病性的一个显著预测指标，并且对于较大的CNV而言，它比已知疾病或单倍剂量不足基因的存在是更好的预测指标。在新生CNV中发现的功能相关基因属于全基因组中发现的所有功能相关基因簇的70%。新生CNV比良性CNV更有可能影响功能簇且影响程度更大（P = 6×10⁻⁴）。此外，这种功能相关基因簇在表型上具有信息性：拥有影响相同功能相关基因簇的CNV的不同患者表现出比预期更相似的表型（P < 0.05）。单个CNV跨越多个功能相似基因在很大程度上解释了这些变异如何发挥其致病作用。
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