WUSTL Researchers ID Elusive Cause of Chiari 1 Brain Malformation

The genetic cause of a common brain malformation has been traced to variations in two genes associated with brain development, according to researchers at Washington University in St. Louis (WUSTL). This news, published in the American Journal of Human Genetics, enables researchers to develop early screening methods before the most serious symptoms arise, and thus intervene.

Chiari 1 malformation is a common, yet poorly understood condition. It is present in about 1% of children and occurs when the cerebellum is displaced through the foramen magnum into the spinal canal, thus placing part of the brain below the base of skull.

Usually, the condition is harmless, causing no – or only minor – medical issues. In 10% of those children, however, Chiari 1 malformation causes problems – severe headaches, neck pain, and issues with hearing, vision, and balance or other neurological manifestations.

Gabriel Haller, Ph.D., an assistant professor of neurosurgery, neurology and of genetics, and his colleagues conducted whole-exome sequencing on 668 children diagnosed with Chiari 1 malformation. It revealed significant enrichment of variants in the chromodomain genes. They found, specifically, “a significant burden of rare, transmitted variants in CHD3… and three loss of function variants in CHD8.”  Many of these variations were de novo, occurring during fetal development and not among family members.    

The researchers also found that children with Chiari 1 who had larger heads (compared to age-matched controls and to population averages provided by the Centers for Disease Control and Prevention) often had CHD variants. Specifically, those whose heads were larger than 95% of children of the same age were four times more likely to be diagnosed with the malformation.

“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,” Haller, senior author of the paper, said in a statement.

For severe symptoms, the Mayo Clinic says surgery is the most common treatment. Its goal is to to reduce the pressure on the brain and to halt further anatomic changes to the brain and spinal canal. Surgery may involve removing bone at the base of the skull, opening the dura mater covering the brain, or removing part of the spinal column to provide more room for the brain or spinal cord.

“A lot of times people have recurrent headaches, but they don’t realize a Chiari malformation is the cause of their headaches,” Haller said. “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.”

“There’s an increased risk for Chiari malformations within families, which suggests a genetic underpinning, but nobody had really identified a causal gene,” Haller said. Of the 232 family members who also underwent gene sequencing, 76 also had Chiari 1 malformation and 156 were unaffected.

The involvement of the CHD8 gene in regulating brain size was confirmed, in further experiments, on transparent zebrafish. 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.

The implications of the finding extend beyond Chiari 1 malformations. Chromodomain genes are involved in regulating multiple sets of genes. As such, they also play a role in a variety of neurodevelopmental conditions, such as autism and developmental delays.

“It’s not well known how chromodomain genes function, since they have such a wide scope of activity and affect so many things at once,” Haller said. “But they are very intriguing candidates for molecular studies, to understand how specific mutations lead to autism or developmental delay or, as in many of our Chiari patients, just to increased brain size without cognitive or intellectual symptoms.

“We’d like to figure out the effects of each of these mutations so that in the future, if we know a child has a specific mutation, we’ll be able to predict whether that variant is going to have a harmful effect and what kind.”

More than 20 clinical trials are underway for this condition, according to ClinicalTrials.gov. Most involve surgical procedures, although a few involve diagnostics. The trial most relevant to drug developers may be a genetics study of 1,000 patients completed by researchers at Duke University in 2017.

While not definitive, it implicated the COL5A2, COL7A1, COL1A2 genes, associated with Ehlers-Danlos syndrome, epidermolysis bullosa, and other conditions; and NRP1, FLT1, VEGFA and VEGFB genes because of their roles in the growth signaling pathway and in placental and vascular development. It confirmed the role of genetics in Chiari malformations and implicated linkages to variations in 21 genes.

Data from a December 2020 study is still being analyzed by the National Institute of Neurological Disorders and Stroke to analyze genetic linkages.

“A lot of kids that have autism or developmental disorders associated with chromodomain genes may have undiscovered Chiari malformations,” Haller said. “The only treatment right now is surgery. Discovering the condition early would allow us to watch, knowing the potential for serious symptoms is there, and perform that surgery as soon as it’s necessary.”