Select single-nucleotide variants in planar cell polarity (PCP) genes are associated with increased risk for neural tube defects (NTDs). However, whether copy number variants (CNVs) in PCP genes contribute to NTDs is unknown. Considering that CNVs are implicated in several human developmental disorders, we hypothesized that CNVs in PCP genes may be causative factors to human NTDs. DNA from umbilical cord tissues of NTD-affected fetuses and parental venous blood samples were collected. We performed a quantitative analysis of copy numbers of all exon regions in the VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3, and PTK7 genes using a CNVplex assay. Quantitative real-time PCR (qPCR) was carried out to confirm the results of CNV analysis. As a result, 16 CNVs were identified among the NTDs. Of these CNVs, 5 loci were identified in 11 NTD probands with CNVs involving DVL2 (exons 1–15), VANGL1 (exons 1–7, exon 8), and VANGL2 (exons 5–8, exons 7 and 8). One CNV (DVL2 exons 1–15) was a duplication and the remaining 15 CNVs were deletions. Eleven CNVs were confirmed by qPCR. One de novo CNV in VANGL1 and one DVL2 were detected from two cases. Compared with unaffected control populations in 1000 Genome, ExAC, MARRVEL, DGV, and dbVar databases, the frequencies of de novo deletion in VANGL1 (1.14%) and de novo duplication in DVL2 (0.57%) were significantly higher in our NTD subjects (p < 0.05). This study demonstrates that de novo CNVs in PCP genes, notably deletions in VANGL1 and gains in DVL2, could contribute to the risk of NTDs.

中文翻译：

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平面细胞极性基因的稀有拷贝数变异与人类神经管缺陷有关。

平面细胞极性（PCP）基因中的选定单核苷酸变体与神经管缺损（NTD）的风险增加相关。但是，PCP基因中的拷贝数变异（CNV）是否有助于NTD是未知的。考虑到CNV与几种人类发育疾病有关，我们假设PCP基因中的CNV可能是人类NTD的致病因素。收集了受NTD感染的胎儿的脐带组织和父母静脉血样本中的DNA。我们对VANGL1，VANGL2，CELSR1，SCRIB，DVL2，DVL3和PTK7中所有外显子区域的拷贝数进行了定量分析基因使用CNVplex分析。进行定量实时PCR（qPCR）以确认CNV分析的结果。结果，在NTD中识别出16个CNV。在这些CNV中，在11个NTD先证者中鉴定出5个基因座，这些CNV涉及DVL2（外显子1-15），VANGL1（外显子1-7，外显子8）和VANGL2（外显子5-8，外显子7和8）。一个CNV（DVL2外显子1-15）是重复的，其余15个CNV是缺失的。通过qPCR确认了11个CNV。一个从头CNV在VANGL1和一个DVL2从检测到2例。与1000个基因组，ExAC，MARRVEL，DGV和dbVar数据库中未受影响的对照人群相比，VANGL1中从头删除的频率（1.14％）和DVL2从头重复（0.57％）在我们的NTD受试者中显着更高（p  <0.05）。这项研究表明，PCP基因中的新生CNV，尤其是VANGL1的缺失和DVL2的增加，可能会导致NTD风险。