TRIO
Chr 5ADtrio Rho guanine nucleotide exchange factor
Also known as: ARHGEF23, MEBAS, MRD44, MRD63, tgat
TRIO encodes a guanine nucleotide exchange factor that activates RHOA and RAC1 GTPases to coordinate actin cytoskeleton remodeling essential for cell migration, neurite outgrowth, and synaptic function in developing neurons. Mutations cause autosomal dominant intellectual developmental disorders that can present with either microcephaly or macrocephaly. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.139), indicating that even heterozygous loss significantly impacts neurodevelopment.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Extremely missense-constrained (top ~0.01%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
TRIO · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Study of the Value of Trio Exome Sequencing in the Etiological Assessment of Specific Non-syndromic Language and Learning Disorders
RECRUITINGAnalyse of Tumour and Constitutional DNA for the Study of the Determinism in Child Neoplasia
ACTIVE NOT RECRUITINGTranscriptomic Approach for the Identification and Prioritization of Genome Variants in Neurodevelopmental Disorders With Malformation
NOT YET RECRUITINGOnline Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
RECRUITINGCP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial
RECRUITINGGenetics of Ventriculo-arterial Discordance
ACTIVE NOT RECRUITINGGenetic Markers of Cardiovascular Disease in Epilepsy
RECRUITINGCancer Predisposition Testing by Family-based Whole-genome Sequencing (WGS) in Every Child With Newly Diagnosed Cancer
RECRUITINGThe Neuroimage Study of the Neuromuscular Disorders.
RECRUITINGGenome Sequencing in the Intensive Care Unit Population
ENROLLING BY INVITATIONThe Benefits of Long-read High-throughput Genomic Sequencing for the Causal Diagnosis of Cerebellar Ataxias
RECRUITINGMultidisciplinary Evaluation and a Genome-wide Analysis in a Cohort of Idiopathic Short Stature Patients
RECRUITINGExternal Resources
Links to major genomics databases and tools