The central nervous system patterning gene variants associated with clinical symptom severity of autism spectrum disorders

J Formos Med Assoc. 2017 Oct;116(10):755-764. doi: 10.1016/j.jfma.2016.11.015. Epub 2017 Jan 9.


Background/purpose: Central nervous system (CNS) patterning genes are recognized as candidate genes for autism spectrum disorders (ASDs) based on neuroimaging and neuropathological evidence. Several genes that regulate CNS development are shown to be associated with ASD. Our previous family-based association study also revealed that a specific haplotype of WNT2 (wingless-type MMTV integration site family member 2) gene was overtransmitted to probands with ASD. Whether the CNS patterning genes moderate the clinical phenotype of ASD is unclear. This study investigated the genetic associations of WNT2, engrailed 2 (EN2), and forkhead box P2 (FOXP2) with the clinical symptom severity.

Methods: The sample included 391 patients (males, 88.3%; mean age±standard deviation, 9.5±4.4 years) diagnosed with ASDs. Tag single nucleotide polymorphisms (SNPs) of EN2, WNT2, and FOXP2 were genotyped. The single-locus and multilocus markers were tested for association.

Results: We found that multilocus markers of WNT2 were associated with stereotyped behaviors whereas the markers of FOXP2 tended to be associated with social deficits. Moreover, an SNP of WNT2 showed a trend to be associated with less inattentive symptoms.

Conclusion: Our findings that WNT2 and FOXP2 may moderate the clinical phenotypes of ASD provide evidence to support the possible universal effect of WNT2 and FOXP2 on neurodevelopmental symptom dimensions. Such findings warrant further validation in other independent samples.

Trial registration: Clinical trial registration identifier: NCT00494754.

Keywords: EN2; FOXP2; WNT2; autism spectrum disorder; phenotype.

Publication types

  • Observational Study

MeSH terms

  • Adolescent
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / physiopathology*
  • Child
  • Child, Preschool
  • Female
  • Forkhead Transcription Factors / genetics*
  • Haplotypes
  • Humans
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Severity of Illness Index
  • Taiwan
  • Wnt2 Protein / genetics*


  • FOXP2 protein, human
  • Forkhead Transcription Factors
  • WNT2 protein, human
  • Wnt2 Protein

Associated data