Search for genetic modifiers of IRF6 and genotype-phenotype correlations in Van der Woude and popliteal pterygium syndromes

Am J Med Genet A. 2013 Oct;161A(10):2535-2544. doi: 10.1002/ajmg.a.36133. Epub 2013 Aug 15.


Van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1-2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype-phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA-binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van de Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van de Woude syndrome.

Keywords: Van der Woude; cleft; lip pit; modifier gene; popliteal pterygium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Alleles
  • Cleft Lip / genetics*
  • Cleft Palate / genetics*
  • Cysts / genetics*
  • Eye Abnormalities / genetics*
  • Family
  • Fingers / abnormalities*
  • Gene Frequency
  • Genetic Association Studies*
  • Genotype
  • Haplotypes
  • Humans
  • Interferon Regulatory Factors / chemistry
  • Interferon Regulatory Factors / genetics*
  • Knee Joint / abnormalities*
  • Lip / abnormalities*
  • Lower Extremity Deformities, Congenital / genetics*
  • Mutation
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Protein Interaction Domains and Motifs / genetics
  • Syndactyly / genetics*
  • Urogenital Abnormalities / genetics*


  • IRF6 protein, human
  • Interferon Regulatory Factors

Supplementary concepts

  • Popliteal Pterygium Syndrome
  • Van der Woude syndrome