These data provide the first mechanistic insight into the heightened caries susceptibility associated with CLP and indicate a direct role for the major CLP gene Irf6 in salivary gland development and a significant role in regulating oral immunity.
Significantly, we also report the identification of 2 unique missense mutations in the NME proteins in patients with CLP (NME1 R18Q in an IRF6 and GRHL3 mutation-negative patient with van der Woude syndrome and NME2 G71V in a patient with nonsyndromic CLP).
After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP).
Among these, variants in interferon regulatory factor 6 (IRF6) cause syndromic orofacial clefting and contribute risk toward isolated cleft lip and palate (1/700 live births).
Irf6 directly regulates Klf17 in zebrafish periderm and Klf4 in murine oral epithelium, and dominant-negative KLF4 variants are present in patients with cleft lip and palate.
DNA variation in Interferon Regulatory Factor 6 (IRF6) causes Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate (CLP).
Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate.
Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P.
The present work steps toward resolving these issues for at least one MSX1 allele: R151S, previously identified in a single Japanese proband with unilateral cleft lip and palate.
This finding underscores the need for evaluating additional variations in IRF6 across multiple populations to better determine its role in nonsyndromic cleft lip and palate.