Genetic Modifiers of Syndromic Orofacial Clefts

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.]]>

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.]]>