Orofacial Cleft 6, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to orofacial cleft-6 (OFC6) is conferred by variation in an enhancer of the IRF6 gene (607199) on chromosome 1q32.

For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic CL/P, see 119530.

In van der Woude syndrome (VWS; 119300), lower lip pits are associated with CL/P or cleft palate only. Since none of these traits is present in all persons who carry the VWS mutation, some individual or familial VWS cases, especially those lacking lip pits, are indiscernible from nonsyndromic CL/P, raising the question of whether allelic variation at the VWS locus could underlie nonsyndromic CL/P. By linkage studies, Hecht et al. (1992) excluded the region of chromosome 1q which carries the van der Woude syndrome as the site of the mutation in this disorder and in isolated cleft palate. Houdayer et al. (2001) could find no evidence for linkage of nonsyndromic CL/P to the VWS locus on 1q32. However, in a parametric analysis using the transmission/disequilibrium test in 106 nonsyndromic CL/P triads (both parents and a child), they found a significant p value of 0.04 for D1S205, supporting involvement of the VWS locus in nonsyndromic CL/P in a complex, modifying/polygenic manner rather than as a monogenic major disease locus.

In a group of 6,755 members from 1,968 families in which at least 1 person had isolated CL/P, Zucchero et al. (2004) found significant association with the V allele at a V274I polymorphism (rs2235371) in the IRF6 gene. Variation at IRF6 was responsible for 12% of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that already had 1 affected child. Zucchero et al. (2004) noted that their findings suggested that the V allele itself was not causal.

Scapoli et al. (2005) investigated 4 markers spanning the IRF6 locus, using the transmission disequilibrium test in a sample of 219 Italian triads of patients and their parents. Strong evidence of linkage disequilibrium was found between markers and disease in both single-allele (rs2235375; P = 0.002) and haplotype (P = 0.0005) analyses in that disease. These findings confirmed the contribution of IRF6 in the etiology of nonsyndromic cleft lip and palate and strongly supported its involvement in populations of European ancestry.

In 51 multiplex families and 184 simplex parent-child trios with nonsyndromic cleft lip and palate and 21 parent-child trios with a positive family history, Blanton et al. (2005) examined the same SNPs as Scapoli et al. (2005) and also detected an altered transmission of IRF6 alleles. Blanton et al. (2005) suggested that IRF6 plays a role in nonsyndromic cleft lip and palate.

Vieira et al. (2007) investigated 172 mother-affected child pairs from the Latin American Collaborative Study of Congenital Malformations (ECLMAC) study for an association of nonsyndromic cleft lip and palate and IRF6. The ECLMAC population was included in the original IRF6 association study published by Zucchero et al. (2004), but no association was detected. Vieira et al. (2007) separated patients with mitochondrial DNA haplotype D (more frequent in Native American subgroups) from other mitochondrial subtypes. An association of IRF6 (specifically the allelic variant V274I) and oral facial cleft was found in patients with mitochondrial haplotypes other than haplotype D. Vieira et al. (2007) suggested that the association of nonsyndromic oral facial cleft and IRF6 in South Americans relates to ancestral origin.

Rahimov et al. (2008) found that the A allele of a common SNP (rs642961, G-A) in an IRF6 enhancer within the 5-prime untranslated region of the IRF6 gene was significantly overtransmitted (p = 1 x 10(-11)) in families with nonsyndromic cleft lip/palate, particularly in those with cleft lip only. There was a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype.

In a hospital-based case-control study of 134 Han Chinese patients with nonsyndromic orofacial clefting (NSOC) and 115 controls matched for age, sex, and residential area, Pan et al. (2010) genotyped 2 polymorphisms in the IRF6 gene, rs2235371 and rs642961. In single-locus analyses, they found that the rs642961 AG and AG/AA genotypes were associated with increased risk of NSOC, especially cleft lip with or without cleft palate (CL/P) and cleft lip with cleft palate (CLP), whereas significantly decreased risks were associated with rs2235371 CT and CT/TT genotypes. In combined analysis using the rs642961 A allele and the rs2235371 C allele as the risk alleles, Pan et al. (2010) found that genotypes containing 2 to 4 risk alleles conferred high risk for NSOC, CL/P, and CLP (odds ratios of 2.15, 2.06, and 2.66, respectively). Analysis of lip skin tissue adjacent to the cleft revealed that rs642961 genotypes were associated with differential levels of IRF6 mRNA and protein expression in an allele-dosage manner. Pan et al. (2010) concluded that IRF6 genetic variants contribute to the etiology of NSOC in the Han Chinese population.