De Novo TRIO Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus

TRIO (c.3232C>T; p.Arg1078Trp, de novo)

De novo missense variant in the Ras-GEF domain of TRIO → disruption of Rac1/RhoA activation → CSF development defect and associated NDD; TRIO previously linked to AD NDD but not to hydrocephalus

A child with syndromic congenital hydrocephalus requiring CSF diversion carries a de novo missense variant in TRIO (c.3232C>T; p.Arg1078Trp), a gene encoding a guanine nucleotide exchange factor (GEF) previously associated with autosomal dominant NDDs. TRIO variants in Ras-GEF domains disrupt coordinated activation of Rac1 and RhoA, pathways essential for neuronal development and ciliogenesis. The genetic architecture of congenital hydrocephalus remains incompletely defined, and TRIO emerges as a contributing gene.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

TRIO expands its phenotypic spectrum beyond pure NDD to a congenital brain malformation requiring neurosurgical management. Clinicians should investigate TRIO in congenital hydrocephalus with associated NDD and sequence Rho-GEF genes. Add to congenital hydrocephalus panels.

major phenotypic expansion (hydrocephalus) +2; de novo AD +2; molecular mechanism described +2; Human Mutation +1; surgical impact (CSF shunting) +1