Kristopher Kahle, MD, PhD, Director of Pediatric Neurosurgery at Mass General is a senior-author of a recent study published in Nature Medicine: Multiomic Analyses Implicate a Neurodevelopmental Program in the Pathogenesis of Cerebral Arachnoid Cysts.

What Question Were You Investigating?

Cerebral arachnoid cysts (ACs)—cerebrospinal fluid-filled sacs in the brain--are the most common space-occupying lesions in the human brain but are very poorly understood.

We performed an integrated analysis of patient-parent exomes, single-cell RNAseq transcriptomes and patient medical record data. Our focus for this study was to elucidate AC pathogenesis, identify genes associated with AC, particularly de novo variants (DNVs). And finally, uncover distinct phenotypic subtypes or clusters.

What Were Your Findings?

We found damaging de novo variants were highly enriched in patients with ACs compared to healthy individuals.

ACs are associated with germline damaging DNVs of chromatin modifying or transcription regulating genes with critical roles in midgestational brain and meningeal development and have significant overlap with autism and epilepsy genes.

While most ACs have historically been considered incidentalomas—incidentally found asymptomatic tumors—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.

We also used artificial intelligence to cluster patients based on similar symptoms and found that clusters with more symptoms had more patients with serious mutations. Many of these mutated genes are also mutated in autism and seizure disorders, both common conditions in AC patients, suggesting some AC symptoms will not improve with surgery because they’re caused by a deeper genetic issue.

What Are the Clinical Implications?

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. Our study suggests whole exome sequencing in these scenarios may help guide treatment decisions and prognostication.

Specifically, finding a damaging DNV in particular genes could discourage neurosurgical intervention because symptoms may be due to a deeper neurodevelopmental pathology rather than AC mass effect. These patients may instead benefit from genetic counselling and early interventions for speech, neurobehavioral, and physical therapies.

What’s Next?

Next steps should include scRNA-seq of AC patient tissue to define impaired transcriptional networks; ChIP-seq to characterize binding proteins and chromatin modifications; and tissue WES to detect somatic variants to understand AC localization and phenotypic diversity.

Paper cited

Kundishora, A. J.*, Allington, G.*, McGee, S.*, Mekbib, K. Y.*, Gainullin, V., Timberlake, A. T., Nelson-Williams, C., Kiziltug, E., Smith, H., Ocken, J., Shohfi, J., Allocco, A., Duy, P. Q., Elsamadicy, A. A., Dong, W., Zhao, S., Wang, Y. C., Qureshi, H. M., DiLuna, M. L., … Torene R. I.#, Jin S. C.#, Kahle, K. T.# (2023). Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts. Nature medicine, 10.1038/s41591-023-02238-2. Advance online publication.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.