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Every year, thousands of children are born with health problems that are caused by changes to their DNA sequence, or genetic code. These changes might have been inherited from their parents, who are often unaffected themselves, and therefore have no idea of what they might be passing on to their children – and therefore, understandably, no idea of how to cope with the consequences. Understanding which genetic changes cause these conditions is critical to helping scientists and doctors inform parents about the conditions their children suffer from, and help to develop new diagnostic and therapeutic strategies to counter the impact this has on the child’s life. In this blog, Kerry Miller, a postdoc in Andrew Wilkie’s lab, explains how her research on a skull deformation condition called craniosynostosis holds the promise to do just that.

You cannot underestimate the comfort for parents of knowing why their child has unexpectedly been born with a specific medical condition. Finding the answer to this question opens new avenues of understanding and gives instruction to the medical professionals who are responsible for the child’s care.

Our research group studies a condition in which children are born with the bones of the skull fused before they should be, known as craniosynostosis. This can result in the brain being unable to grow and expand to its full capacity, which in turn can cause an abnormal head shape and increased internal pressure on the growing brain.

Craniosynostosis affects one child in approximately every 2250, and so is relatively commonly seen by children’s doctors. The condition can occur on its own, or in combination with other problems such as intellectual disability. Doctors who see these patients routinely send samples of their blood to check the DNA sequence in a number of genes known to cause this condition.

Alterations (mutations) in six genes (in addition to other larger chromosomal alterations) are known to cause around 25% of cases of craniosynostosis. But because of the increasing number of genes that are being identified that may also cause the condition (that may therefore contribute to the other 75% of cases), identifying the appropriate genetic tests for each patient becomes increasingly difficult. Therefore, standard routes of testing often miss the primary reason underlying the condition.

In this new study, published in the Journal of Medical Genetics, we looked at 40 different children with craniosynostosis, using new “deep sequencing” technology to read the regions of their DNA containing the genes in order to pinpoint the reasons why their skulls have developed abnormally. Each child had previously been tested for, and had shown no alteration in, the standard suspected genetic causes (including larger chromosomal variations). In addition to trying to unravel why specific DNA changes cause this condition in these individuals, we can also improve our understanding of how the human skull normally develops.

In the 40 childrenwho were included in this study, the genetic cause of their craniosynostosis was found in 15, a success rate of 37.5%. Not only did this provide an explanation of the cause of the condition in these patients for the first time, but in some cases itunexpectedly identified the potential for additional medical problems to develop, and therefore also helped to anticipate these through appropriate preventive measures.

In at least five instances, the findings were entirely unanticipated, but had a direct and immediate impact on the decisions made in the medical care of the child and their family. These ranged from guiding reproductive decisions to select for a specific sex of embryo (i.e. girl or boy) during in vitro fertilisation so as to avoid having another affected child born with the same condition, to extensive monitoring involving many teams of specialists, for example for heart problems or severe infections, that are commonly associated with the particular genetic change identified.

This study highlights the impact of using these new deep DNA sequencing methods to identify the underlying genetic cause in cases that would otherwise have eluded routine clinical testing. In addition the project helped to identify several new genes associated with craniosynostosis for the first time – discoveries that will help to improve diagnosis and impact patient management strategies even further in the future.