New York, Dec 29 : Researchers have found that a common brain disorder called Chiari 1 malformation can be caused by variations in two genes involved in brain development.
The condition occurs when the lowest parts of the brain are found below the base of the skull.
About one in 100 children has this malformation, but most of the time such children grow up normally and no one suspects a problem.
But in about one in 10 of those children, the condition causes headaches, neck pain, hearing, vision and balance disturbances, or other neurological symptoms.
In some cases, the disorder may run in families, but scientists understood little about the genetic alterations that contribute to the condition until now.
The new study also revealed that children with unusually large heads are four times more likely to be diagnosed with Chiari 1 malformation than their peers with normal head circumference.
"There's an increased risk for Chiari malformations within families, which suggests a genetic underpinning, but nobody had really identified a causal gene," said senior author Gabriel Haller, Assistant Professor at Washington University School of Medicine in St.
"We were able to identify two causal genes, and we also discovered that people with Chiari have larger head circumference than expected.
It's a significant factor, and easy to measure. If you have a child with an enlarged head, it might be worth checking with your pediatrician."
The findings, published in the American Journal of Human Genetics, could lead to new ways to identify people at risk of developing Chiari 1 malformation before the most serious symptoms arise.
It also sheds light on the development of the common but poorly understood condition.
"A lot of times people have recurrent headaches, but they don't realise a Chiari malformation is the cause of their headaches," said Haller.
"And even if they do, not everyone is willing to have brain surgery to fix it.
We need better treatments, and the first step to better treatments is a better understanding of the underlying causes."
If people start experiencing severe symptoms like chronic headaches, pain, abnormal sensations or loss of sensation, or weakness, the malformation is treated with surgery to decompress the Chiari malformation.
To identify genes that cause Chiari 1 malformation, Haller and colleagues sequenced all the genes of 668 people with the condition, as well as 232 of their relatives.
Of these relatives, 76 also had Chiari 1 malformation and 156 were unaffected.
Sequencing revealed that people with Chiari 1 malformation were significantly more likely to carry mutations in a family of genes known as chromodomain genes.
Several of the mutations were de novo, meaning the mutation had occurred in the affected person during fetal development and was not present in his or her relatives.
In particular, the chromodomain genes CHD3 and CHD8 included numerous variants associated with the malformation.
Further experiments in tiny, transparent zebrafish showed that the gene CHD8 is involved in regulating brain size.
When the researchers inactivated one copy of the fish's chd8 gene, the animals developed unusually large brains, with no change in their overall body size.
Chromodomain genes help control access to long stretches of DNA, thereby regulating expression of whole sets of genes.
Since appropriate gene expression is crucial for normal brain development, variations in chromodomain genes have been linked to neurodevelopmental conditions such as autism spectrum disorders, developmental delays, and unusually large or small heads.