Department of Pathology (Cytogenetics), Child and Family Research Institute, University of British Columbia (UBC), 950 West 28th, Room 3060, Vancouver, BC, V5Z 4H4, Canada.
Hum Genet. 2010 Aug;128(2):179-94. doi: 10.1007/s00439-010-0837-0. Epub 2010 May 29.
Array CGH enables the detection of pathogenic copy number variants (CNVs) in 5-15% of individuals with intellectual disability (ID), making it a promising tool for uncovering ID candidate genes. However, most CNVs encompass multiple genes, making it difficult to identify key disease gene(s) underlying ID etiology. Using array CGH we identified 47 previously unreported unique CNVs in 45/255 probands. We prioritized ID candidate genes using five bioinformatic gene prioritization web tools. Gene priority lists were created by comparing integral genes from each CNV from our ID cohort with sets of training genes specific either to ID or randomly selected. Our findings suggest that different training sets alter gene prioritization only moderately; however, only the ID gene training set resulted in significant enrichment of genes with nervous system function (19%) in prioritized versus non-prioritized genes from the same de novo CNVs (7%, p < 0.05). This enrichment further increased to 31% when the five web tools were used in concert and included genes within mitogen-activated protein kinase (MAPK) and neuroactive ligand-receptor interaction pathways. Gene prioritization web tools enrich for genes with relevant function in ID and more readily facilitate the selection of ID candidate genes for functional studies, particularly for large CNVs.
比较基因组杂交技术能够检测出 5-15%的智力障碍患者存在致病性拷贝数变异(CNV),使其成为发现智力障碍候选基因的有前途的工具。然而,大多数 CNV 包含多个基因,因此很难确定导致智力障碍病因的关键疾病基因。我们使用比较基因组杂交技术在 255 名先证者中发现了 47 个以前未报道的独特 CNV。我们使用五个生物信息学基因优先级网络工具来优先考虑 ID 候选基因。通过将我们的 ID 队列中每个 CNV 的整基因与特定于 ID 或随机选择的训练基因集进行比较,创建了基因优先级列表。我们的研究结果表明,不同的训练集仅适度改变基因优先级;然而,只有 ID 基因训练集导致优先考虑的基因与相同从头 CNV 中非优先考虑的基因相比,具有神经系统功能(19%)显著富集(7%,p<0.05)。当五个网络工具协同使用并包含丝裂原活化蛋白激酶(MAPK)和神经活性配体-受体相互作用途径中的基因时,这种富集进一步增加到 31%。基因优先级网络工具富集了与 ID 相关功能的基因,并更便于选择 ID 候选基因进行功能研究,特别是对于大型 CNV。