Van der Woude syndrome is the most common cause of syndromic orofacial clefting. It is characterised by the presence of lip pits, cleft lip and/or cleft palate. It is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Several mutations in the interferon regulatory factor 6 (IRF6) gene have been found in VWS families, suggesting that this gene is the primary locus. We screened for mutations in this gene in three families in our population. There was a recurrent nonsense mutation within exon 9 of the gene for a Malay family consisting of five affected members with different presentations. We also found a co-segregating rare polymorphism which would result in a non-synonymous change 23 bases downstream of the nonsense mutation. This polymorphism was present in <1% of the Malay subjects screened, but was not found among the Chinese and Indians in our population. For another family, a 396C↷T mutation (R45W in the DNA-binding domain) was found in the proband, although the possibility of a genetic defect elsewhere could not be excluded because his mother and twin sister (both unaffected) also had this variant. In the third case with complete absence of family history, a de novo deletion spanning the whole IRF6 gene was detected in the child with VWS. This case of haploinsufficiency caused disruption of orofacial development but not other organ systems as the child has no other medical or developmental abnormalities despite the deletion of at least five other genes.

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