Rare copy number variations of planar cell polarity genes are associated with human neural tube defects

Neurogenetics. 2020 Jul;21(3):217-225. doi: 10.1007/s10048-020-00613-6. Epub 2020 May 9.


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.

Keywords: CNVplex assay; Copy number variant; De novo variants; Neural tube defects; Planar cell polarity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • Carrier Proteins / genetics
  • Cell Adhesion Molecules / genetics
  • Cell Polarity / genetics*
  • DNA Copy Number Variations*
  • Developmental Disabilities / genetics*
  • Dishevelled Proteins / genetics
  • Exons
  • Gene Deletion
  • Gene Dosage
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Proteins / genetics
  • Mutation
  • Neural Tube Defects / genetics*
  • Real-Time Polymerase Chain Reaction
  • Receptor Protein-Tyrosine Kinases / genetics
  • Risk
  • Tumor Suppressor Proteins / genetics
  • Umbilical Cord / metabolism


  • CELSR1 cadherin, human
  • Cadherins
  • Carrier Proteins
  • Cell Adhesion Molecules
  • DVL2 protein, human
  • DVL3 protein, human
  • Dishevelled Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SCRIB protein, human
  • Tumor Suppressor Proteins
  • VANGL1 protein, human
  • VANGL2 protein, human
  • PTK7 protein, human
  • Receptor Protein-Tyrosine Kinases