[Show abstract][Hide abstract]ABSTRACT: Cleft lip with or without cleft palate (CL/P) is a common birth defect throughout the world. Linkage studies have shown interferon regulatory factor 6 (IRF6) to be associated with CL/P in multiple populations, including one in Honduras. It is unknown, however, whether rare sporadic mutations or common variants are the cause of this association, and reports exist supporting both hypotheses. Thus, it is important to determine the cause for this association in a Honduran population.
Case-control and family-based association studies.
Families with two or more members affected by CL/P were identified. We collected DNA from affected and unaffected family members (608 total), and from 100 gender-matched controls from Honduras. We sequenced the exons of IRF6 for mutations in probands and controls. All patients were genotyped for single nucleotide polymorphisms (SNPs) rs642961 and rs2235371, which are proposed to have potential biological significance to IRF6 expression and function.
We found no mutations in IRF6 in our CL/P probands. We found a risk association with the G allele of rs2235371 in both case-control (P = .01) and family-based association (P = .01) studies. We found no association with either allele of rs642961.
This study suggests that common variants, rather than rare mutations, are the cause for association between IRF6 and nonsyndromic CL/P. rs2235371, but not rs642961, shows association with CL/P, suggesting a functional role for this polymorphism in our Honduran population. rs642961 has been previously reported to have an effect in other populations, suggesting that different populations may be affected by different polymorphisms.
Full-text available · Article · Aug 2011 · The Laryngoscope
[Show abstract][Hide abstract]ABSTRACT: Van der Woude syndrome (VWS) is an autosomal dominant inherited disease characterized by lower lip pits, cleft lip and/or cleft palate. Missense, nonsense and frameshift mutations in IRF6 have been revealed to be responsible for VWS in European, Asian, North American and Brazilian populations. However, the mutations responsible for VWS have not been studied in Central American populations. Here, we investigated the role of IRF6 in patients with VWS in a previously unstudied Honduran population. IRF6 mutations were identified in four out of five VWS families examined, which strongly suggests that mutations in IRF6 are responsible for VWS in this population. We reported three novel mutations and one previously described mutation. In the first family, a mother and daughter both exhibited a p.N88I mutation in the DNA-binding region of IRF6 that was not present in unaffected family members. In the second, we found a unique p.K101QfsX15 mutation in the affected patient, leading to a frameshift and early stop codon. In the third, we identified a p.Q208X mutation occurring in exon 6. In the fourth, we found a nonsense mutation in exon 9 (p.R412X), previously described in Brazilian and Northern European populations. In the fifth, we did not identify any unique exonic missense, nonsense or frameshift mutations. This study reports the first cases of IRF6 mutations in VWS patients in a Central American population, further confirming that the causal link between IRF6 and VWS is consistent across multiple populations.
Full-text available · Article · Mar 2011 · Molecular Medicine Reports
[Show abstract][Hide abstract]ABSTRACT: Interferon regulatory factor 6 (IRF6), the gene that causes van der Woude syndrome (VWS), is a candidate gene for nonsyndromic cleft lip with or without cleft palate (NSCLP) because a number of studies have supported an association between NSCLP and single nucleotide polymorphisms (SNPs) in IRF6 in several populations. This project investigated the contribution of IRF6 to NSCLP in the Honduran population, a previously unstudied group with a high prevalence of NSCLP.
Family-based joint linkage and association study.
A set of five SNPs in and around IRF6 previously reported to be associated with NSCLP were tested for association with NSCLP in 276 affected and unaffected Honduran individuals from 59 families with at least two members affected by clefting and at least one member with confirmed NSCLP.
We observed support of linkage for three SNPs-rs1856161, rs2235371, and rs2235377-under a dominant model (log of odds [LODs] = 1.97, 1.56, 1.73, respectively). Subsequent single-point, haplotype, and joint linkage and association analyses continued to support the association with NSCLP (P < or = .05) at these three SNPs. When analysis was restricted to NSCLP cases, excluding cleft palate only cases, support for association strengthened.
This is the first study to demonstrate that three candidate SNPs within IRF6 are significantly associated with NSCLP in the Honduran population, providing the first genetic clue to NSCLP observed in the Honduran population and confirming findings from populations in other parts of the world. Further studies are needed to identify the putative variant(s).