IRF6 – Van der Woude syndrome

Van der Woude syndrome (VWS) is an autosomal dominant orofacial clefting disorder characterized by paramedian lower‐lip pits and cleft lip and/or palate. Heterozygous mutations in IRF6 were first reported in Northern European VWS kindreds and subsequently across diverse populations, including a Thai pedigree with a novel exon 9 deletion (PMID:12632105), an Italian family carrying the c.651G>A (p.Trp217Ter) stop‐gain (PMID:15013698), and a Turkish family with an Arg84Gly substitution (PMID:15647839).

IRF6 mutations have been identified in 209 of 307 VWS families (68%) across Japanese, Scandinavian, Thai and other cohorts, with pathogenic variants nonrandomly clustering in exons 3, 4, 7 and 9 (PMID:19282774). These findings underscore an autosomal dominant inheritance with high penetrance and variable expressivity, with affected relatives demonstrating tight cosegregation of IRF6 alleles and phenotype.

Case series and pedigree analyses report over 200 unique IRF6 variants—missense, nonsense, frameshift, splice‐site and large copy‐number alterations—across more than 350 unrelated families. For example, the recurrent c.250C>G (p.Arg84Gly) missense allele was found in affected siblings and an obligate carrier exhibiting nonpenetrance in a Turkish kindred (PMID:15647839). Intragenic deletions and whole‐gene microdeletions further establish haploinsufficiency as the predominant pathogenic mechanism.

Functional studies in Irf6‐null mice reveal severe defects in keratinocyte proliferation, skin, limb and craniofacial morphogenesis, implicating disrupted periderm differentiation in VWS (PMID:17041601). Complementary zebrafish assays demonstrate that human IRF6 mRNA rescues irf6 maternal‐null periderm rupture, whereas patient‐derived frameshift and nonsense alleles fail to do so, confirming loss‐of‐function effects (PMID:28945736).

Collectively, genetic and experimental data fulfill ClinGen criteria for a definitive gene–disease relationship. IRF6 testing enables accurate diagnosis of VWS, informs recurrence risk in families, and guides early multidisciplinary care.

Key Take-home: IRF6 haploinsufficiency causes autosomal dominant VWS; comprehensive IRF6 sequencing and copy-number analysis should be standard in orofacial cleft diagnostics.

References

• International journal of molecular medicine • 2003 • A novel mutation, 1234del(C), of the IRF6 in a Thai family with Van der Woude syndrome. PMID:12632105
• Mutation Research • 2004 • A novel mutation of the IRF6 gene in an Italian family with Van der Woude syndrome. PMID:15013698
• International journal of molecular medicine • 2005 • Van Der Woude syndrome: variable penetrance of a novel mutation (p.Arg84Gly) of the IRF6 gene in a Turkish family. PMID:15647839
• Genetics in Medicine • 2009 • Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. PMID:19282774
• Nature Genetics • 2006 • Abnormal skin, limb and craniofacial morphogenesis in mice deficient for interferon regulatory factor 6 (Irf6). PMID:17041601
• PLoS Genetics • 2017 • Rapid functional analysis of computationally complex rare human IRF6 gene variants using a novel zebrafish model. PMID:28945736

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