Genetic Insights into a Fluid-Related Brain Condition in Newborns

Early detection and treatment of congenital cerebral ventriculomegaly (CCV)—when a fetus’s fluid-filled brain ventricles swell due to a condition called hydrocephalus—can help clinicians prevent developmental or neurological disabilities in affected infants. New research led by investigators at Mass General Brigham Neuroscience Institute has identified some of the gene mutations involved in this condition, which is often seen alongside autism and other developmental disorders. The findings are published in Science Translational Medicine.

“A significant number of patients have developmental delay, with up to 10% exhibiting autism spectrum disorder. Our findings link CCV to neurodevelopmental disorders and position CCV as a potential early neuroimaging correlate of autism risk,” said senior author Kristopher T. Kahle, MD, PhD, the Chief of Pediatric Neurosurgery at the Mass General Brigham Neuroscience Institute. Kahle is also the Nicholas T Zervas Endowed Chair in Neurosurgery at Harvard Medical School and an investigator at the Broad Institute of MIT and Harvard.

For the study, Kahle and colleagues analyzed genetic data from approximately 2,700 children with congenital cerebral ventriculomegaly and their parents to identify potential causative mutations, and they paired their findings with information from brain development datasets and mouse models.

The team found that about 25% of cases were associated with rare and damaging gene mutations, often in genes that are important for how brain cells grow and organize during early brain development. In mice, silencing these genes caused the ventricles to swell by impairing both brain fluid movement and the structure of the cerebral cortex, which is responsible for higher-level functions such as reasoning, memory, and language.

The findings suggest that congenital cerebral ventriculomegaly is not just a fluid circulation issue but often reflects underlying developmental problems in the brain itself. The authors suggest combining prenatal imaging with genetic testing to identify cases before birth.

“Neurosurgical intervention is often life-saving and effective, but, in some cases, it fails to improve ventricular size or neurodevelopmental outcomes while exposing patients to future infections and long-term dependence on draining shunts,” said Kahle. “Genomic testing might eventually refine patient selection and identify whether surgical or nonsurgical care is best in individual situations.”

Authorship: In addition to Kahle, Mass General Brigham authors include Garrett Allington, Evan Dennis, Qiang Li, Neel H. Mehta, Kedous Y. Mekbib, Phan Q. Duy, Baojian Fan, Hannah Smith, and William C. Davalan. Additional authors include Stephen McGee, Izuho Hatada, Matthew C. Weston, Amy N. Shore, Erin R. Cullen, Tyrone DeSpenza, Amrita Singh, Danielle Miyagishima, Emre Kiziltug, Andrew T. Hale, Carol Nelson-Williams, Andrés Moreno-de-Luca, Ekkehard M. Kasper, Adam J. Kundishora, Bryan W. Luikart, Shozeb Haider, Seth L. Alper, Richard P. Lifton, and Sheng Chih Jin.

Disclosures: McGee is an employee and shareholder of GeneDx, LLC. The other authors declare that they have no competing interests.

Funding: This work was supported by the National Institutes of Health (NIH) (R01 NS111029, R01 NS117609, R01 NS109358, R01 NS131610, and R01 NS110945) and by the Rudi Schulte Research Institute Foundation (grant 2023A005805).

Paper cited: Allington G et al. “Developmental genetic determinants of the human cerebrospinal fluid-ventricular system” Science Translational Medicine DOI: 10.1126/scitranslmed.aec4386