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Impaired folate metabolism can result in neural tube defects (NTDs). However, the precise nature of the relationship between low folate status and NTDs remains unclear. Using an array\u2010comparative genomic hybridization (aCGH) assay, we investigated whether CNVs could be detected in the NTD embryonic neural tissues of methotrexate (MTX)\u2010induced folate dysmetabolism pregnant C57BL\/6 mice and confirmed the findings with quantitative real\u2010time PCR (qPCR). The CNVs were then comprehensively investigated using bioinformatics methods to prioritize candidate genes. We measured dihydrofolate reductase (DHFR) activity and concentrations of folate and relevant metabolites in maternal serum using enzymologic method and liquid chromatography\/tandem mass spectrometry (LC\/MS\/MS). Three high confidence CNVs on XqA1.1, XqA1.1\u2010qA2, and XqE3 were found in the NTD embryonic neural tissues. Twelve putative genes and three microRNAs were identified as potential susceptibility candidates in MTX\u2010induced NTDs and possible roles in NTD pathogenesis. DHFR activity and 5\u2010methyltetrahydrofolate (5\u2010MeTHF), 5\u2010formyltetrahydrofolate (5\u2010FoTHF), and S\u2010adenosylmethionine (SAM) concentrations of maternal serum decreased significantly after MTX injection. These findings suggest that CNVs caused by defects in folate metabolism lead to NTD, and further support the hypothesis that folate dysmetabolism is a direct cause for CNVs in MTX\u2010induced NTDs. \u00a9 2014 Wiley Periodicals, Inc. 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