Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the aetiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research.

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Cleft lip and palate: understanding genetic and environmental influences.

Breakthroughs in the genetics of orofacial clefting.

Purpose: The interferon regulatory factor 6 (IRF6), the gene that causes van der Woude syndrome has been shown to be associated with nonsyndromic cleft lip with or without palate in several populations. This study aimed to confirm the contribution of IRF6 to cleft lip with or without palate risk in additional Asian populations.Methods: A set of 13 single nucleotide polymorphisms was tested for association with cleft lip with or without palate in 77 European American, 146 Taiwanese, 34 Singaporean, and 40 Korean case-parent trios using both the transmission disequilibrium test and conditional logistic regression models.Results: Evidence of linkage and association was observed among all four populations; and two specific haplotypes [GC composed of rs2235373-rs2235371 (p.V274I) and AAG of rs599021-rs2235373-rs595918] showed the most significant over- and undertransmission among Taiwanese cases (P = 9 × 10−6 and P = 5 × 10−6, respectively). The AGC/CGC diplotype composed of rs599021-rs2235373-rs2013162 showed almost a 7-fold increase in risk among the Taiwanese sample (P < 10−3). These results confirmed the contribution of this gene to susceptibility of oral clefts across different populations; however, the specific single nucleotide polymorphisms showing statistical significance differed among ethnic groups.Conclusion: The high-risk genotypes and diplotypes identified here may provide a better understanding of the etiological role of this gene in oral clefts and potential options for genetic counseling.

https://ir.ymlib.yonsei.ac.kr/bitstream/22282913/96053/1/T200700781.pdf

Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations

Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: pEurope = 6.50 × 10−06, pMayan = .0151; rs3758249: pEurope = 2.41 × 10−05, pMayan = .0299), no association was found in nsCPO (p > .05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P (p =...

Strong Association of Variants around FOXE1 and Orofacial Clefting

Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. 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. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for casecontrol analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p,10 26 ). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p,10 26 ). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10 26 for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6-TGFA interaction found in humans.

/pdf/interaction-between-irf6-and-tgfa-genes-contribute-to-the-16fogq1kbf.pdf

Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate

BACKGROUND

Cleft lip with or without cleft palate (CL/P) is one of the most common craniofacial malformations, with a complex and multifactorial etiology. Because of the genetic heterogeneity of facial clefts, the aim of this study was to investigate the contribution of previously reported candidate genes and chromosomal loci to the risk of CL/P in the Polish population.



METHODS

We performed an analysis of 18 polymorphisms of FOXE1, IRF6, MSX1, PAX9, TBX10, FGF10, FGFR1, TGFα, TGFβ3, SUMO1, and the chromosomal region 8q24 in a group of 175 patients with CL/P and a properly matched control group.



RESULTS

Highly significant results were observed for the IRF6 rs642961 variant and the 8q24 region's rs987525 (odds ratio [OR]AG+AAvsGG, 1.635; 95% confidence interval [CI], 1.153–2.319; p = 0.005; and ORAC+AAvsCC, 1.962; 95% CI, 1.382–2.785; p = 1.4 × 10−4, respectively). For rs987525, the results were also significant after correction for multiple comparisons. Borderline association with an increased risk of CL/P was also identified for the SUMO1 locus (rs2350350; ORCGvsGG, 1.580; 95% CI, 1.056–2.363; p = 0.025).



CONCLUSIONS

Our findings confirmed that genetic variants of IRF6 and the polymorphism located in the 8q24 gene desert are strongly involved in the etiology of facial clefts in the Polish population sample. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Association between genetic variants of reported candidate genes or regions and risk of cleft lip with or without cleft palate in the polish population.

Patrycja Paradowska

Papers

Association between genetic variants of reported candidate genes or regions and risk of cleft lip with or without cleft palate in the polish population.