Functional Consequence of IRF6 Variants in Van der Woude Syndrome

Year: 2026

Type: article

Abstract: Van der Woude syndrome (VWS) is the most common syndromic form of orofacial clefts (OFCs). The heritability of VWS is largely (~70%) explained by variants in the IRF6 gene. Experimental studies to confirm genetic variant effects are essential but are time intensive and expensive. Advancing next-generation sequencing techniques has made it possible to identify genetic variation quicker than their causal effects in disease processes can be ascertained. Therefore, employing computational tools to reliably predict their causal effects is crucial for advancing translational research. We conducted Sanger sequencing of the IRF6 gene in 46 VWS cases across 34 families to identify likely causal missense variants. We then assessed structure-informed stability changes to the IRF6 protein when these variants were incorporated into the protein, using DDGun3D. We compared DDGun3D predictions to results from previous experimental studies. Among four variants previously shown to prevent functional rescue in zebrafish, only the variant IRF6(NM_006147.4):c.881T>C, shown to cause rupture of zebrafish embryo, exhibited a high free energy change (∆∆Gfold = 3.5 kcal/mol), indicating that substantial predicted thermodynamic destabilization does not capture all disruptive function of IRF6. Our study demonstrates the utility of a protein structure-based computational approach for functional variant interpretation, providing a complementary method for studying genetic variation. Integrating computational predictions with experimental data can enhance our understanding of genetic conditions. However, success depends on fully elucidating protein structures, which is an active area of research.

Source: Genes

DOI: 10.3390/genes17101223

Institutions: University of Iowa, King's College London, University of Michigan, Creighton University, University of KwaZulu-Natal, Kwame Nkrumah University of Science and Technology, Addis Ababa University, University of Lagos, University of Puerto Rico System, University of Dundee

Language: English

Topic: Cleft Lip and Palate Research

Subfield: Oral Surgery

Field: Dentistry

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,137

Funders: National Institute of Dental and Craniofacial Research, National Institute on Minority Health and Health Disparities

Awards: Genetic and Environmental Risks for Oral Clefts in Puerto Rican Hispanics, Hispanics in Research Capability: SoHP & SOM Partnership (HIREC), Genetic studies of nonsyndromic clefts in populations of African Descent., Refining the Genetic and Genomic Architecture of Non‐syndromic Orofacial Clefts, Puerto Rico Clinical and Translational Research Consortium (PRCTRC)

OpenAlex ID: W7216595255