Van Der Woude Syndrome - Genetics

Genetics

Van der Woude syndrome is inherited as an autosomal dominant disease caused my a mutation in a single gene with equal distribution between the sexes. The disease has high penetrance at about 96% but the phenotypic expression varies from lower lip pits with cleft lip and cleft palate to no visible abnormalities. Approximately 88% of VWS patients display lower lip pits, and in about 64% of cases lip pits are the only visible defect. Reported clefting covers a wide range including submucous cleft palate, incomplete unilateral CL, bifid uvula, and complete bilateral CLP. VWS is the most common orofacial clefting syndrome, accounting for 2% of CLP cases.

The majority of VWS cases are caused by haploinsufficiency due to mutations in the interferon regulatory factor 6 gene (IRF6) on chromosome 1 in the 1p32-p41 region known as VWS locus 1. A second less common causative locus is the gene WDR65 at position 1p34, known as VWS locus 2. IRF6 contains two non-coding and seven coding exons and is part of a family of nine transcription factors with a highly conserved helix-turn-helix DNA binding domain called the Smad-interferon regulatory factor binding domain (SMIR). Any mutations in either the coding or non-coding IRF6 exons result in Van der Woude syndrome. Due to the wide range of expressivity, it is also believed that other unidentified loci contribute to disease development.

An example of the clear phenotypic variability is a monozygotic twin study conducted by Jobling et al. (2010). Two monozygotic female twins had the same IRF6 mutation; however Twin A was born with a bilateral cleft lip, whereas Twin B had bilateral lip pits and no orofacial clefting. Both twins were diagnosed with VWS. The twins' father had lip pits alone and a family history of CLP, CP, CL, and/or lip pits. Both twins were diagnosed with VWS. Polymerase chain reaction (PCR) amplification was done for all exons of IRF6, and a missense mutation was discovered in exon 4. The tyrosine in the normal protein at this position is conserved across mammals, frogs, and chickens, so despite the fact that it was a previously unreported mutation, it was expected to be deleterious. This study is not the first case of different phenotypes occurring between monozygotic twins. Possible causes of phenotypic variability include variations in the intrauterine environment, epigenetic differences, or chance effects.