Abstract
BackgroundNeural 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.MethodsThe 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.ResultsFifty-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.ConclusionsEvidence 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.
Highlights
Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors
Non-DGV copy number variants (CNVs) were Enriched in NTD Samples A total of 85 cases (NTD-affected embryos) and 75 controls were collected
The detailed categories of NTD cases were listed on Table 1
Summary
Neural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. 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. Neural tube defects (NTDs) are common and severe birth defects. Severe NTDs, such as craniorachischisis and anencephaly, are directly related to high morbidity and mortality. Less severe forms, such as open spina bifida, lead to life-long disabilities and impose a tremendous burden on affected families [1]. The prevalence of NTDs is high in China, with approximately 27.4 per 10,000 pregnancies reported [3]. The Shanxi Province in China has the highest NTD occurrence at the rate of 138.7–199.4/10,000 [4,5]
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