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De Novo TRIO Missense Variants Disrupt Ras-GEF Domains and Cause Congenital Ventriculomegaly and Hydrocephalus
Neel H Mehta1, Evan Dennis1, Garrett Allington1,2
1Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, harvard.edu.
Insights
Pathogenic variants in the TRIO gene are linked to congenital hydrocephalus (CH) and congenital ventriculomegaly (CV). This study identifies TRIO as a key gene in syndromic CH, expanding its known role in neurodevelopmental disorders.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Congenital hydrocephalus (CH), marked by congenital ventriculomegaly (CV), affects 0.5-1 per 1000 live births, necessitating pediatric neurosurgery.
- The genetic underpinnings of CH remain largely undefined, despite its prevalence.
- The TRIO gene is known for autosomal dominant neurodevelopmental disorders with variable head circumference.
Purpose of the Study:
- To investigate the role of TRIO gene variants in patients with syndromic congenital hydrocephalus and congenital ventriculomegaly.
- To determine if TRIO is a significant genetic factor in the etiology of syndromic CV/CH.
Main Methods:
- Exome sequencing was performed on a cohort of 2,697 patient-parent trios with CV/CH.
- Identification and characterization of de novo TRIO variants.
- In silico structural modeling and analysis of single-nucleus transcriptomic data from the developing human neocortex.
- Systematic literature review to identify additional affected individuals.
Main Results:
- Five new unrelated probands with de novo TRIO variants were identified in the CV/CH cohort, with two novel substitutions in the Ras-GEF1 domain.
- Significant gene-level enrichment for protein-damaging de novo TRIO variants was observed (adjusted p = 6.12 × 10^-5).
- All affected individuals presented with CV, often with developmental delay and brain abnormalities.
- In silico modeling indicated variants destabilize critical TRIO Ras-GEF domains.
- TRIO expression is enriched in multipotent progenitor populations in the developing neocortex.
- A literature review identified six additional individuals with de novo TRIO variants and CV/CH.
Conclusions:
- Pathogenic de novo TRIO variants are a significant cause of syndromic congenital hydrocephalus and congenital ventriculomegaly.
- This study expands the phenotypic spectrum of TRIO-related disorders to include CV/CH.
- TRIO should be considered in the genetic evaluation of patients with syndromic CV/CH.
Abstract:
Congenital hydrocephalus (CH), characterized by congenital ventriculomegaly (CV), affects approximately 0.5-1 per 1000 live births and is a common cause of pediatric neurosurgical intervention, yet its genetic architecture remains incompletely defined. We report a child with syndromic CH requiring cerebrospinal fluid diversion who harbored a pathogenic de novo missense variant in TRIO (c.3232C > T; p.(Arg1078Trp)), a gene previously associated with autosomal dominant neurodevelopmental disorders featuring variable head circumference. This case prompted systematic evaluation of TRIO variation in our CV/CH cohort (2,697 patient-parent trios) using exome sequencing. We identified five additional unrelated probands with de novo TRIO variants, including two novel substitutions affecting the same residue within the Ras-GEF1 domain (p.(Glu1299Lys) and p.(Glu1299Gly)), yielding significant gene-level enrichment for protein-damaging de novo variants (adjusted p = 6.12 × 10-5). 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 TRIO Ras-GEF domains required for Rho GTPase activation. Analysis of single-nucleus transcriptomic data from the developing human neocortex revealed enrichment of TRIO expression in multipotent progenitor populations. A systematic literature review identified six additional individuals with TRIO 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 TRIO variation to include CV/CH and support TRIO as a clinically relevant gene in the genetic evaluation of syndromic CV/CH patients.
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