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A recent Yale study has identified new genes associated with congenital hydrocephalus, a neurological disease.

The paper, which was published on Oct. 19, is based on the exome sequencing —  the sequencing of the protein-coding regions of genes in a genome — of 381 patients with congenital hydrocephalus, or CH. In the past, CH has been considered a disorder of cerebrospinal fluid, or CSF, management, rather than a genetic disorder of neurodevelopment. The mainstay of treatment is invasive neurosurgery to drain the fluid. The study, however, found that many patients with CH have a genetic disease, rather than simply a CSF handling problem.

“Hydrocephalus is traditionally seen as a disorder of cerebrospinal fluid,” said Adam Kundishora, one of the study’s authors and a neurological-surgery resident at Yale. “Fundamentally, it’s thought of as a plumbing disorder. However, the genes that we identified were not genes that dealt with the production or movement of CSF.”

According to Kundishora, the genes that were identified determine the fate of neural progenitor cells, which are responsible for the structure and development of the brain itself.

As of right now, he said, all of the patients who present with CH are thought to have a problem with CSF and are treated as such. However, the study found that this may not always be the case and that the condition is sometimes a disorder of early anatomical brain development.

According to Weilai Dong, one of the study’s authors and a doctoral student in genetics, the researchers found that the disease has a strong genetic predisposition.

“We found many rare damaging genetic mutations in those patients through whole exome sequencing,” Dong said. “And what is striking is we found 22 percent of patients can be explained by a genetic factor.”

The implications of this finding is a change in both the diagnosis and the treatment of CH. The genetic component of the disease, she said, will serve as a basis for personalized treatment or management for patients with CH.

According to Kristopher Kahle, a pediatric neurosurgeon and the principal investigator on the study, CH is normally treated with a shunt placement — a neurosurgical operation that drains the CSF from the brain and deposits it into another body cavity for absorption. This procedure, he said, has a very high rate of reoperation and morbidity, and most people do not escape the disease without some sort of complication.

The mortality rate of shunt procedures for hydrocephalus is between 0.3 and 0.8 percent, and an average of 23 percent of patients need to have two reoperations.

According to Kahle, the CH patients without a fluid disorder may benefit from forgoing surgery — instead, they may benefit more from speech and physical therapy, or management by a neuropsychologist. Those patients would then be able to avoid the high risk of the surgery.

According to Kundishora, exome sequencing is not currently the standard practice. Instead, CH patients are diagnosed by a neurosurgeon after presenting with a symptom such as enlarged brain ventricles, seizures or macrocephaly — or an overly large head. The possible sequencing of all CH patients in the future, however, could help the diagnoses be much more specific, which would allow for more targeted treatment.

Being able to take a genetic test and get insight into your child’s potential condition could help treat the patient more specifically for the condition that they have,” Kahle said.

The next step in the research process, Kahle said, is to sequence the exome of more patients. By increasing their sample size, the researchers could harness more statistical power to determine the exact subgroups of CH diagnoses. A larger cohort will allow for the identification of more genes that are potentially associated with the disease, which will in turn create a strong classification system for CH.

According to Dong, the group is currently working on expanding their cohort by recruiting more patients. While 381 patients were sequenced in the study, Dong is hoping they will soon have over 500.

As well as finding more patients, Dong thinks the group may focus on developing an understanding of how the disease functions on a cellular and molecular level through “transcriptional analysis and functional experiments.”

Hydrocephalus is the most common reason for brain surgery in children.

Kaitlin Flores | kaitlin.flores@yale.edu