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Transl. Med."],"published-print":{"date-parts":[[2026,7,8]]},"abstract":"<jats:p>Primary enlargement of the cerebrospinal fluid (CSF)\u2013filled 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 \u201chand-in-glove\u201d 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.<\/jats:p>","DOI":"10.1126\/scitranslmed.aec4386","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T17:58:12Z","timestamp":1783533492000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Developmental genetic determinants of the human cerebrospinal fluid\u2013ventricular system"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5458-6129","authenticated-orcid":true,"given":"Garrett","family":"Allington","sequence":"first","affiliation":[{"name":"Department of Neurology, New York Presbyterian Hospital and Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA."},{"name":"Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, 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