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We report a child with syndromic CH requiring cerebrospinal fluid diversion who harbored a pathogenic de novo missense variant in\n                    <jats:italic>TRIO<\/jats:italic>\n                    (c.3232C &gt; T; p.(Arg1078Trp)), a gene previously associated with autosomal dominant neurodevelopmental disorders featuring variable head circumference. This case prompted systematic evaluation of\n                    <jats:italic>TRIO<\/jats:italic>\n                    variation in our CV\/CH cohort (2,697 patient\u2013parent trios) using exome sequencing. We identified five additional unrelated probands with de novo\n                    <jats:italic>TRIO<\/jats:italic>\n                    variants, including two novel substitutions affecting the same residue within the Ras\u2010GEF1 domain (p.(Glu1299Lys) and p.(Glu1299Gly)), yielding significant gene\u2010level enrichment for protein\u2010damaging de novo variants (adjusted\u2009\n                    <jats:italic>p<\/jats:italic>\n                    = 6.12 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ). All affected individuals exhibited CV, frequently accompanied by developmental delay and additional structural brain abnormalities. In silico structural modeling predicted that associated variants destabilize critical\n                    <jats:italic>TRIO<\/jats:italic>\n                    Ras\u2010GEF domains required for Rho GTPase activation. Analysis of single\u2010nucleus transcriptomic data from the developing human neocortex revealed enrichment of\n                    <jats:italic>TRIO<\/jats:italic>\n                    expression in multipotent progenitor populations. A systematic literature review identified six additional individuals with\n                    <jats:italic>TRIO<\/jats:italic>\n                    de novo variants and reported CV or CH, including an unrelated patient with the same p.(Arg1078Trp) substitution. Together, these findings expand the phenotypic spectrum associated with pathogenic\n                    <jats:italic>TRIO<\/jats:italic>\n                    variation to include CV\/CH and support\n                    <jats:italic>TRIO<\/jats:italic>\n                    as a clinically relevant gene in the genetic evaluation of syndromic CV\/CH patients.\n                  <\/jats:p>","DOI":"10.1155\/humu\/8870037","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T15:18:39Z","timestamp":1777303119000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["De Novo\n                    <i>TRIO<\/i>\n                    Missense Variants Disrupt Ras\u2010GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus"],"prefix":"10.1155","volume":"2026","author":[{"given":"Neel H.","family":"Mehta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9741-9275","authenticated-orcid":false,"given":"Evan","family":"Dennis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5458-6129","authenticated-orcid":false,"given":"Garrett","family":"Allington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2508-387X","authenticated-orcid":false,"given":"Kedous Y.","family":"Mekbib","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3182-2966","authenticated-orcid":false,"given":"Andrew 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