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Sequencing Study Suggests Mutations Underlying Cerebral Cysts May Inform Severity, Treatment Options

NEW YORK – New research has uncovered genetic contributors to cerebrospinal fluid-filled pockets known as cerebral arachnoid cysts (ACs), including de novo mutations with apparent ties to AC symptoms and severity — insights expected to provide a look at the biological underpinnings of the cysts and the anticipated effectiveness of neurosurgical interventions.

"While most ACs have historically been considered 'incidentalomas,' our study suggests they may be a telling radiographic sign of genetically mediated defects in brain development that may manifest with neurodevelopmental or neurobehavioral pathology, and warrant genetic testing and neurobehavioral follow-up," co-first author Kedous Mekbib, a neurosurgery researcher affiliated with Yale University School of Medicine and Massachusetts General Hospital, explained in an email.

As they reported in Nature Medicine on Monday, he and his colleagues used exome sequencing to assess more than 1,600 blood or saliva samples from 617 individuals with radiographically confirmed cerebral ACs, along with their unaffected parents. Together with an algorithm trained for processing natural language in individuals' health histories — and single-cell RNA sequencing profiles on nearly 153,000 individual cells from human brain or mouse meningeal samples — the exomes highlighted enrichment for de novo variants in the cerebral AC-affected individuals.

In particular, the team explained, the results pointed to an overrepresentation of de novo germline genetic variants in a handful of chromatin modifier genes and transcription-regulating genes influencing neural and meningeal development pathways active in the brain during midgestation.

Likewise, the germline damaging DNVs tended to turn up in genes previously implicated in conditions such as autism spectrum disorder or epilepsy, Mekbib explained, while unsupervised phenotype clustering uncovered ties between specific protein-damaging DNVs and disease clusters marked by varying disease severity.

"Notably, all seven of the exome-wide significant AC genes are highly expressed in the fetal brain and associated with OMIM-cataloged Mendelian diseases with neurodevelopmental phenotypes," the researchers wrote, noting that these and other results suggest that ACs might "represent anatomic sequelae or radiographic vestiges of more fundamental defects in brain development."

More broadly, the identification and characterization of cerebral AC-associated germline DNVs may help to distinguish between cases that will benefit from neurosurgical interventions to address cerebrospinal fluid buildup, seizure, motor, and other cerebral AC symptoms and those that may be better served by genetic counseling and early speech, neurobehavioral, and physical therapy interventions, the authors explained, noting that surgical interventions currently have "varied, unpredictable, and sometimes devastating outcomes."

"While the neurosurgical management of ACs causing hydrocephalus or significant mass effect is widely accepted, the decision to operate on ACs for seizures, developmental delay, behavioral or psychiatric symptoms has been unclear," Mekbib said, suggesting exome sequencing "may help guide treatment decisions and prognostication" in such circumstances.

"Specifically, finding a damaging DNV in particular genes could discourage neurosurgical intervention," he explained, "because symptoms may be due to a deeper neurodevelopmental pathology rather than AC mass effect."