Submission Details

TRIO encodes a Rho guanine nucleotide exchange factor (RhoGEF) that plays essential roles in neuronal development. Variants in TRIO were first reported in relation to autosomal dominant syndromic intellectual disability (ID) in 2016 (Ba et al., PMID: 26721934). Numerous variants in TRIO, including nonsense, frameshift and missense variants, have been reported, with most variants occurring de novo. Pathogenic variants in TRIO are associated with neurodevelopmental disorders, including ID and autism spectrum disorder. Other features include gastrointestinal problems, facial and skeletal dysmorphism. Missense variants cluster in two domains, the spectrin repeat and the RAC1-activating GEFD1. Individuals with variants in the spectrin domain have severe ID associated with macrocephaly and recognizable facial dysmorphism, whereas individuals with GEFD1 variants display milder ID and microcephaly (PMID: 32109419). Functional studies show that spectrin variants result in hyper-activation of RAC1, while GEFD1 variants cause hypo-activation of RAC1. RAC1 activation levels are correlated with the head size of affected individuals. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 25 probands in 3 publications (PMIDs: 26721934, 27418539, 32109419). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by TRIO’s role in neurogenesis, migration and synapse formation; protein interaction between TRIO and proteins involved in ID (RAC1, FLNA), functional alterations in non-patient cells, and mouse and xenopus models (4 points). In summary, TRIO is definitely associated with syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 11/03/2021 (SOP Version 8).