Research Spotlight: A Genetic Cause of Brain Ventricular Enlargement in Patients with Congenital Hydrocephalus and Autism Spectrum Disorder

Kristopher Kahle, MD, PhD, Director of Pediatric Neurosurgery at Massachusetts General Hospital and the Nicholas T. Zervas Associate Professor of Neurosurgery at Harvard Medical School, is co-corresponding author of a new study in PNAS, Pathogenic Variants in Autism Gene KATNAL2 Cause Hydrocephalus and Disrupt Neuronal Connectivity by Impairing Ciliary Microtubule Dynamics.

Summary: The enlargement of the fluid-filled spaces in the brain (called ventricles) occurs in patients with congenital hydrocephalus (CH) and may also occur in patients with autism spectrum disorder (ASD).

We found a genetic cause of brain ventricular enlargement in patients with CH and ASD that will help further our understanding of these disorders for improved diagnosis and treatment strategies.

What Question Were You Investigating with Your Study?

What is the molecular basis of ventriculomegaly in a genetic subset of CH patients harboring pathogenic variants in the ASD-associated gene KATNAL2?

We wanted to learn how KATNAL2 variants impact brain development, particularly cerebrospinal fluid (CSF) dynamics and neuronal connectivity, thereby contributing to our understanding of both CH and ASD pathogenesis.

What Were the Results?

We identified a genetic association between human KATNAL2 variants and ventriculomegaly and then recapitulated ventriculomegaly in Katnal2 knockout and humanized mutant mice.

Investigations of Katnal2 mutant mice revealed altered intraventricular CSF homeostasis and parenchymal neuronal connectivity due to disrupted microtubule dynamics of primary cilia in fetal radial glia and their post-natal ependymal and neuronal descendants.

Our study yielded valuable insights into the role of ventricular primary cilia during early brain development, shedding light not only on the underlying mechanisms of ventriculomegaly but also on a potential sub-cellular locus where CSF homeostasis and brain connectivity converge.

What are the Clinical Implications and Next Steps?

These results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.

Paper Cited:

DeSpenza, T., Jr, Singh, A., Allington, G., Zhao, S., Lee, J., Kiziltug, E., Prina, M. L., Desmet, N., Dang, H. Q., Fields, J., Nelson-Williams, C., Zhang, J., Mekbib, K. Y., Dennis, E., Mehta, N. H., Duy, P. Q., Shimelis, H., Walsh, L. K., Marlier, A., Deniz, E., … Luikart, B. W. (2024). Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics. Proceedings of the National Academy of Sciences of the United States of America, 121(27), e2314702121. https://doi.org/10.1073/pnas.2314702121