IRF6 – Van der Woude Syndrome 1

IRF6, encoding the transcription factor interferon regulatory factor-6, is causally implicated in autosomal dominant Van der Woude syndrome 1 (VWS1) with a Definitive ClinGen gene–disease validity classification. This assignment is supported by pathogenic IRF6 variants identified in over 549 unrelated families with VWS or popliteal pterygium syndrome, each demonstrating co-segregation and consistent clinical features (PMID:23154523).

Genetic Evidence

Van der Woude syndrome 1 follows an autosomal dominant inheritance pattern with high penetrance. In the recent case report, a novel heterozygous missense variant c.970T>C (p.Ser324Pro) was identified in a proband and transmitted from her affected father, consistent with vertical transmission (PMID:40084670). Additional segregation of IRF6 variants has been documented in more than 549 pedigrees, confirming familial transmission and phenotype concordance (PMID:23154523).

Variant Spectrum and Case Series

Pathogenic IRF6 alleles include missense (e.g., p.Arg84Leu), nonsense (e.g., p.Arg412Ter), frameshift, splice-site, and regulatory enhancer variants, reflecting a broad mutation spectrum. Over 194 unique missense or nonsense variants have been reported in VWS1 families, with recurrent hotspots in the DNA-binding domain (PMID:23154523). The novel c.970T>C (p.Ser324Pro) variant expands this landscape and underscores the critical role of the C-terminal domain in IRF6 function (PMID:40084670).

Functional Evidence

Irf6-null mice exhibit abnormal skin, limb, and craniofacial development with disrupted keratinocyte differentiation—recapitulating key features of VWS1 and demonstrating haploinsufficiency as a mechanism of disease (PMID:17041601). Rapid zebrafish rescue assays further classify human IRF6 missense variants by their ability to restore periderm integrity, confirming functional impairment of loss-of-function alleles and refining variant pathogenicity assessments (PMID:28945736).

Conflicting Evidence

Large population sequencing studies reveal that IRF6 coding variants are exceedingly rare in controls, with only two potentially pathogenic alleles observed in over 6,000 individuals, minimizing concerns about false positive associations (PMID:23154523). No studies to date have refuted the IRF6–VWS1 association or identified alternative causative genes in IRF6-positive pedigrees.

Integration and Clinical Utility

Collectively, the robust segregation of IRF6 variants across hundreds of pedigrees, the extensive spectrum of deleterious alleles, and concordant in vivo functional data establish a Definitive clinical validity for IRF6 in Van der Woude syndrome 1. Genetic testing of IRF6 should be prioritized in patients presenting with cleft lip and/or palate with lower lip pits and related ectodermal anomalies. Accurate identification of IRF6 variants informs genetic counseling, recurrence risk estimation, and guides prenatal or preimplantation diagnostic strategies.

References

• Genetics and molecular biology • 2025 • Van der Woude syndrome and amniotic band sequence: A clue to a common genetic etiology? A case report. PMID:40084670
• Nature Genetics • 2006 • Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). PMID:17041601
• Genetics in Medicine • 2013 • Comparative analysis of IRF6 variants in families with Van der Woude syndrome and popliteal pterygium syndrome using public whole-exome databases. PMID:23154523
• PLoS Genetics • 2017 • Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model. PMID:28945736

Evidence Based Scoring (AI generated)