Capital Institute of Pediatrics, Beijing, China.
PLoS One. 2013;8(1):e54492. doi: 10.1371/journal.pone.0054492. Epub 2013 Jan 17.
Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs.
The genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined.
Fifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24-5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27-8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways.
Evidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.
神经管缺陷（NTDs）是由遗传和环境因素共同作用导致的最常见的出生缺陷之一。目前，尽管据报道高达 70%的人类 NTDs 归因于遗传因素，但对于 NTDs 的遗传基础知之甚少。在这里，我们对一组中国 NTD 患者进行了全基因组拷贝数变异（CNVs）检测，以研究 CNVs 在 NTD 发病机制中的潜在作用。
对 85 例 NTD 病例和 75 例匹配的正常对照的基因组 DNA 进行全基因组 CNVs 分析。对每组的非 DGV（基因组变异数据库）CNVs 进行进一步分析，以研究其与 NTDs 的相关性。检查非 DGV CNVs 中的基因含量以及参与的途径。
在病例和对照组中分别检测到 55 个和 26 个非 DGV CNVs。其中，40 个和 19 个 CNVs 涉及基因（基因 CNV）。与对照组相比，NTD 患者中非 DGV CNVs 和非 DGV 基因 CNVs 的数量明显更多（41.2%对 25.3%，p<0.05 和 37.6%对 20%，p<0.05）。非 DGV 基因 CNVs 与 NTDs 的风险增加 2.65 倍（95%CI：1.24-5.87）相关。有趣的是，NTD 患者的非 DGV CNVs 中涉及 41 个纤毛基因，与对照组相比，这在病例中明显富集（24.7%对 9.3%，p<0.05），与 NTDs 的风险增加 3.19 倍（95%CI：1.27-8.01）相关。通路分析进一步表明，两个纤毛发生途径，紧密连接和蛋白激酶 A 信号通路，是与 NTD 特异性 CNVs 相关的主要经典途径，这两个新途径与已知的 NTD 途径相互作用。
全基因组 CNV 研究的证据表明，基因 CNVs，特别是纤毛发生 CNVs 与 NTDs 相关，两个纤毛发生途径，紧密连接和蛋白激酶 A 信号通路，是 NTD 发病机制中潜在的途径。
