Developmental genetic determinants of the human cerebrospinal fluid-ventricular system.

Authors

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

Published in

Science translational medicine. Volume 18. Issue 857. Pages eaec4386. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

Primary enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the "hand-in-glove" development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

PMID:
42418557
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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