A REMARKABLE pair of twins in Brazil have led to the discovery of a gene that may play a role in the most common forms of cleft lip and palate.
The twins were noticed by a doctor because one was born with a form of cleft lip and palate known as Van der Woude syndrome, while the other was not. This was puzzling because VWS is usually a hereditary condition. Yet genetic tests showed the twins were identical, meaning they both developed from the same fertilised egg. So the gene mutation responsible for VWS must have arisen after the egg split.
“That meant the twins should be identical everywhere, except for one mutation,” says Jeff Murray at the University of Iowa in Iowa City, whose lab had been searching for this gene for 16 years. “That simplified the hunt and gave us courage to do a lot of DNA sequencing to finally find it.”
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And that’s just what Murray and his collaborators around the world did. They discovered a mutation in a gene that codes for a little-studied protein called interferon regulatory factor 6, or IRF6 (Nature Genetics, DOI: 10.1038/ng985).
“The twin strategy was a gamble. There are good reasons it might not have worked,” says Constantine Stratakis, chief of genetics and endocrinology at the US National Institute of Child Health and Human Development near Washington DC. “But it paid off big this time.”
Mutations in over a dozen genes have already been linked to other forms of cleft lip and palate. But while VWS only accounts for 2 per cent of cleft lip and palate cases, it closely resembles the “non-syndromic” form, which accounts for 70 per cent of cases. The causes of the non-syndromic condition are unclear. There seems to be a genetic basis, but it is also influenced by factors during pregnancy such as smoking, lack of folic acid and excessive drinking.
Murray’s team has now started investigating the possibility that IRF6 also plays a role in this condition. Proteins similar to IRF6 are involved in the immune system’s response to viruses, for instance, so Murray is checking epidemiological databases to see if there is any link with infections during pregnancy.
Around 1 in 700 people are born with a cleft lip and palate. Although surgery and other therapies can minimise the effects, it can still be a distressing condition, especially for children whose speech and appearance are affected, and some people choose not to have children rather than risk passing the problem on. The discovery of the mutations involved will make it possible to screen embryos during IVF, and test people worried they might pass the condition on to their children. “I’m sure it will play a role in genetic counselling,” Murray says.