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Another limitation was the ethnic heterogeneity of the samples, which included families from Brazil, Colombia, the Philippines, and the United States, but 33% of the families were from unspecified populations (Supplemental eTable II in Supporting Information Online). We also examined the types and locations of IRF6 mutations to determine if these contributed to specific VWS phenotypes. We would have predicted that truncation mutations, which are most obviously damaging to the protein, would be associated with more severe phenotypes such as CLP. We did not find such an association, suggesting that both missense and truncation mutations result in haploinsufficiency of IRF6 and result in similar phenotypes. The exception to this is the strong association between missense [http://www.selleckchem.com/products/BIBW2992.html selleck kinase inhibitor] mutations in the DNA-binding domain (and more specifically, residues that contact DNA) with limb defects. This result was expected and was consistent with previous data showing a strong association between mutations at residues contacting DNA and PPS [de Lima 2009]. In addition, we found a nonsignificant association between mutations in the protein-binding domain and lip pits only. There was no association when we grouped all individuals with lip pits together, suggesting that mutations in the protein-binding domain may not be related to the development of lip pits but rather may protect against the development [https://en.wikipedia.org/wiki/PTPRJ PTPRJ] of clefts. Although statistically we only detected associations that met nonstringent (P?[http://www.selleckchem.com/products/Dasatinib.html Dasatinib purchase] to include Pbx-1, 2, and 3 regulating p63 through Wnt9b and Wnt3 [Ferretti 2011]. We propose that these genes and TP63, which regulates IRF6 through the enhancer MCS9.7 [Rahimov et al., 2008; Moretti et al., 2010; Thomason et al., 2010; Fakhouri et al., 2012], be investigated in future modifier studies. The MCS9.7 enhancer was not associated in this study (through rs642961); however, its expression pattern does not completely recapitulate the expression of IRF6 [Fakhouri 2012], suggesting that IRF6 expression is controlled by additional regulatory elements. It is possible that variation in these yet to be discovered regulators and regulatory elements contribute to the variable expressivity of VWS and PPS. We also showed that the mutation-negative families are less likely to have individuals with cleft lip. The causal mutations in the IRF6-mutation-negative families may lie in these undiscovered regulatory elements. A second locus for VWS has been reported on 1p34 by linkage [Koillinen 2001], and a mutation has been described in WDR65, although not in the linkage family [Rorick 2011].