Digenic variants of planar cell polarity genes in human neural tube defect patients

Mol Genet Metab. 2018 May;124(1):94-100. doi: 10.1016/j.ymgme.2018.03.005. Epub 2018 Mar 18.


Neural tube defects (NTDs) are considered to be a complex genetic disorder, although the identity of the genetic factors remains largely unknown. Mouse model studies suggest a multifactorial oligogenic pattern of inheritance for NTDs, yet evidence from published human studies is surprisingly absent. In the present study, targeted next-generation sequencing was performed to screen for DNA variants in the entire coding regions and intron-exon boundaries of targeted genes using DNA samples from 510 NTD cases. These candidate genes were PCP genes, including VANGL1, VANGL2, CELSR1, SCRIB, DVL2, DVL3 and PTK7. Candidate variants were validated using Sanger sequencing. A total of 397 single nucleotide variants(SNVs) were identified with a mean depth of approximately 570×. Of these identified SNVs, 74 were predicted to affect protein function and had a minor allele frequency of <0.01 or unknown. Among these 74 missense SNVs, 10 were identified from six NTD cases that carried two mutated genes. Of the six NTD cases, three spina bifida cases and one anencephaly case carried digenic variants in the CELSR1 and SCRIB gene; one anencephaly case carried variants in the CELSR1 and DVL3 gene; and one spina bifida case carried variants in the PTK7 and SCRIB genes. Three cases that parental samples were available were confirmed to be compound heterozygous. None of the digenic variants were found in the 1000 genome database. The findings imply that genetic variation might interact in a digenic fashion to generate the visible NTD phenotypes and emphasize the importance of these genetic interactions in the development of NTDs in humans.

Keywords: Digenic variants; Neural tube defects; PCP pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • Carrier Proteins / genetics
  • Cell Adhesion Molecules / genetics
  • Cell Polarity / genetics*
  • DNA Mutational Analysis
  • Dishevelled Proteins / genetics
  • Genetic Variation*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Proteins / genetics
  • Mutation
  • Neural Tube Defects / blood
  • Neural Tube Defects / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Receptor Protein-Tyrosine Kinases / genetics
  • Tumor Suppressor Proteins / genetics


  • 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