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Study Description
Reduced penetrance and variable expressivity are common, but poorly understood, features of most monogenic diseases. Genetic modifiers are possible factors to contribute to this phenotypic variability and blur the traditional distinction between monogenic and complex disease. This study focuses on the most common orofacial cleft syndrome (Van der Woude syndrome, VWS) and nonsyndromic orofacial clefts (OFCs), which intersect both in phenotype and in genetic etiology, as a model to understand reduced penetrance and variable expressivity. VWS occurs in 1 in 35,000 individuals and accounts for 2% of all OFCs. The features of VWS include an OFC and/or lower lip pits, but 15% of VWS patients present with an isolated OFC, making them indistinguishable from nonsyndromic OFC patients. Mutations in the genes IRF6 or GRHL3 cause VWS, but approximately 20% of VWS patients currently lack a molecular diagnosis. Furthermore, there are few genotype-phenotype correlations for known mutations and patient phenotypes. By contrast, GWAS of nonsyndromic OFCs have identified a number of risk factors, some of which we have shown increase risk for specific types of OFCs or act as modifiers of OFC subtypes. Whole genome sequencing will be used to identify the remaining genetic mutations for VWS, determine the relationship between those genes/regions with nonsyndromic OFCs, and identify rare and common modifiers of VWS and OFC phenotypes. These analyses will provide further insight into the genetic architecture of VWS and OFCs and will serve as a model for exploring links between other Mendelian disorders that share phenotypes with complex traits.
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Study Inclusion/Exclusion Criteria
To be eligible for sequencing individuals had to have a clinical diagnosis of Van der Woude syndrome (orofacial cleft and/or lip pits).
Study History

Van der Woude syndrome was initially linked to 1q32 and mapped to the IRF6 gene. Pathogenic IRF6 mutations of all types, representing at least 229 different alleles have been reported. One family with VWS was linked to 1p34 and was mapped by exome sequencing to the GRHL3 gene. Mutations in IRF6 account for ~75% of VWS cases while mutations in GRHL3 account for an additional 5% of families. VWS shares the high phenotypic heterogeneity described for nonsyndromic OFCs. Beyond the three primary types of overt clefts (CL, CLP, and CP), OFCs can be further subdivided into bilateral and unilateral clefts, affecting either the left or right side of the upper lip. VWS has additional layers of phenotypic heterogeneity due to the presence or absence of lip pits and congenitally missing teeth. The causes of this variability in phenotype are largely unknown. This study builds on years of recruitment of families with Van der Woude syndromic and syndromic OFCs by investigators at the University of Iowa and at Emory University's Emory Cleft Project.

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Diseases/Traits Related to Study (MeSH terms)
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Study Attribution
  • Principal Investigator
    • Elizabeth J. Leslie, PhD. Emory University, Atlanta, GA, USA.
  • Co-Investigator
    • Jeffrey C. Murray, MD. University of Iowa, Iowa City, IA, USA.
  • Funding Source
    • R01-DE028432. National Institutes of Health, Bethesda, MD, USA.
  • Genotyping (or Sequencing) Center
    • Center for Inherited Disease Research (CIDR). Johns Hopkins University, Baltimore, MD, USA.