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Clinical photograph of a child with Craniosynostosis (Twigg & Wilkie, AJHG 2015)

Craniofacial malformations, i.e. those that affect the head and face, make up over one-third of all congenital birth defects. These types of abnormalities can also have the greatest impact on patients, who often have concerns about their appearance that can have a significant impact on their quality of life. Professor Andrew Wilkie has been part of the WIMM for over 20 years, where his Clinical Genetics Group try to understand the molecular basis of a type of skull malformation called craniosynostosis. In this blog, Aimee Fenwick tells us how far our understanding of this devastating disease has come in the past ten years.

The top of the human skull is actually made up from five different bones. When we are born, these bones are separate, but in patients with craniosynostosis they fuse together prematurely, which can have severe ramifications for the affected individual.

This means that the brain, which grows extremely rapidly from birth, has nowhere to expand and so pushes against the skull leading to an abnormal head shape. In some cases, the pressure in the brain can lead to serious problems such as learning disability, seizures and blindness.

Thankfully, modern surgery such as that routinely carried out by the Oxford Craniofacial Unit can reduce the risk of these serious complications, and at the same time improve patients’ appearance and psychological wellbeing.

A key goal of Professor Wilkie’s research is to understand what causes this condition to develop in the first place – and therefore better understand how to help patients affected by it.

The advent of new DNA sequencing technology (as discussed in this recent blog post) has enabled the changes, or mutations, that underlie conditions like craniosynostosis to be identified for hundreds of rare conditions. In two recent reviews (one published in Human Molecular Genetics, and one in the American Journal of Human Genetics) Andrew Wilkie and Steve Twigg looked at the advances that have been made into our understanding of craniofacial genetic diseases over the last few years.

Since 2013, ten new genes (distinct sections of the DNA that contain the information to make specific proteins) have been identified that are linked to the development of craniofacial disease – five of which were identified by the WIMM Clinical Genetics group. In addition to these, a further seven genes have been identified that are suspected to be associated with cleft lip and cleft palate.

The head is the most complex structure of the human body, and so any mistake in the tightly regulated and highly co-ordinated process of development can lead to an abnormal appearance.

By identifying the genes that control this process, scientists and doctors can start to gain a full understanding of how the human head develops. In turn, this can help to uncover further potential disease genes with related roles in craniofacial development.

While this isn’t likely to translate into miracle cures in the near future, because the faulty genes affect the formation of the head early in development before the baby is born, improving diagnosis of these conditions is a huge help to the families involved.

Early knowledge can lead to the right social and educational assistance (if needed), and also enables proper genetic counselling. This means that families can decide whether or not to have more children with a full understanding of the risks of passing on the same disease to them.

For clinicians it means that they have a better understanding of their patient. For example, depending on which gene is affected, the patient may need to have more than one operation, or there may be other risks associated with a particular condition.

What is for certain is that we are now better placed than ever to identify the genetic causes of craniofacial malformations, and translate this knowledge directly to the clinic. So far, ten of the genes discovered by Andrew Wilkie’s lab have been approved for diagnostic testing within the NHS.

This means that more families are able to get a full, detailed and comprehensive diagnosis of the condition affecting their child, and the information they need to prepare for the future. Which, ultimately, is the purpose of the research undertaken by scientists like those at the WIMM.

Post edited by Bryony Graham, Steve Twigg and Andrew Wilkie.