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

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 case-control 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<10-6). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10-6). 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 = 10-6 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. © 2012 Letra et al

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Details of the SNPs investigated in this study.

a<p>According to the USCS Genome Browser on Human March 2006 Assembly (hg18).</p>b<p>Assay-on-demand.</p

Results of linkage disequilibrium analyses for the investigated markers in the Brazilian Caucasian population (406 cases and 285 controls).

<p>r² is above the diagonal; D’ is below the diagonal.</p

Results of interaction analyses of associated <i>TGFA</i> and <i>IRF6</i> marker alleles in the family dataset (861 simplex and multiplex families) comprising 7047 people stratified by population origin and cleft types.

**<p>Cleft types, CL: cleft lip only; CLP: cleft lip with or without cleft palate; CLCLP: cleft lip only + cleft lip with or without cleft palate; MX: mixed cleft types; CP: cleft palate only.</p>***<p>Populations: Caucasians from USA and Europe.</p

Summary of the association analysis in Brazilian Caucasians according to each cleft subphenotype with dental anomalies.

*<p>Unilateral CL/P with agenesis or microdontia of the maxillary lateral incisor on the noncleft side.</p>**<p>P≤0.0008 indicates significant difference (in bold).</p>†<p>For both genotype and allele.</p

Results for interaction of <i>TGFA</i> C3827T and <i>IRF6</i> V274I marker alleles in the Brazilian Caucasian cases (N = 406) and controls (N = 285).

*<p>Mantel-Haenszel test; p≤0.05 indicates statistical difference (in bold).</p

Summary of the analysis with the Latvian cases (N = 154) with cleft lip/palate and 30 case-parent trios (90 individuals) from CEPH.

*<p>The <i>IRF6</i> marker used was rs2013162. The <i>TGFA</i> marker used was rs3732253.</p

Loss of Tgfa expression in embryos that lack <i>Irf6</i>.

<p>Expression of Tgfa (A,A′), Irf6 (B, B′) and merge (C, C′) in coronal sections of E14.5 wild type murine embyos. Tgfa and Irf6 expression colocalized to oral and nasal epithelium and remaining medial edge epithelium. Magnification was 10× (A–C) and 40× (A′–C′) for boxed regions in panels A–C. No expression was observed for Tgfa and Irf6 in coronal sections of E14.5 embryos that lack <i>Irf6</i> (D). Regions of higher magnification are indicated (D′, D′′). Abbreviations are palate (p), tongue (t), nasal septum (ns).</p

Baseline clinical characteristics of the Brazilian population.

<p>Baseline clinical characteristics of the Brazilian population.</p