People affected by the disorder, called craniosynostosis, are born with or develop abnormally shaped heads. This is caused by the plates of the skull joining together earlier than normal, which in turn can cause increased pressure in the skull and hearing, vision and breathing difficulties. Restricted brain growth and developmental problems are common.
Craniosynostosis affects around one in 2,200 children and in 21 percent of cases it is due to an identifiable genetic defect. But Andrew Wilkie, professor of pathology at Oxford University, the leader of the study, estimates that around a third of all cases are in fact caused by a genetic fault.
'I had the suspicion that there were other unidentified genes out there that were implicated and that still needed to be discovered', he says, 'and that's where this study has come in'.
The genes identified by the research have independent functions and this is reflected in the clinical picture. The non-bony tissues that join the skull plates are called sutures and only some of them will join too early in patients with craniosynostosis. 'The two genes we identified affect the skull in very different ways and give distinctly different patterns of suture fusion from each other', explains Professor Wilkie.
The research leading to one of the genes being identified began with DNA analysis of a family in which both children had craniosynostosis but its cause was unknown. The ERF gene was put forward as a potential candidate and this was confirmed when mutations in ERF were identified in an additional 11 samples from over 400 other patients, but not in analysis of healthy controls.
In most of these cases patients had been born with normally shaped skulls and the craniosynostosis only became apparent in early to middle years of childhood. On the other hand, patients with mutations in the other gene identified by the researchers, TCF12, usually required surgery within the first two years of life.
The researchers estimate that mutations in either ERF of TCF12 are responsible for up to three percent of all cases of craniosynostosis. In both cases knowledge of the genetic cause is helpful as families and care teams can better appreciate the characteristics and risks of the condition, including risks of inheritance.
But Professor Wilkie says that in the case of the ERF mutations, where the problem manifests later on, 'knowledge of the mutation would be very valuable. It would alert a surgeon to the fact there was an underlying problem leading to the sutures not working properly. The surgeon would know to keep a very close eye on the child. They couldn't say that the child seemed fine and simply discharge them from follow-up'.
The research was partially supported by the National Institute for Health Research (NIHR). Professor Wilkie says that the NIHR's Comprehensive Clinical Research Network (CCRN) was essential to the success of the study which involved genetic information, resources and staff from four centres of excellence for craniosynostosis.
'Combined, those four centres represent a unique resource', Professor Wilkie comments. 'Before the NIHR-CCRN structure had been designed and put in place, it would have been impossible to have drawn on that resource as we did here'.
Both studies are published in Nature Genetics.