Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature

Abstract

The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype‐to‐phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244‐2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype‐to‐phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.

Heterozygosity for neurodevelopmental disorder-associatedTRIOvariants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice

“…Rac1 activity is well known to play a functional role in metabolism, particularly by mediating glucose-stimulated insulin secretion from pancreatic islet beta-cells (97–102), so it is not surprising that chronic alterations in Rac activity may contribute to weight changes in Trio +/K1431M and +/K1918X mice. While most studies of specific Trio variants have focused on neuronal effects, expression of Trio in other tissues may explain the body weight changes observed in these mice, as well as the musculoskeletal abnormalities associated with TRIO variation in humans (8, 29, 31, 46).…”

“…Trio deficiency also leads to aberrations in long-term potentiation (LTP), as Trio-Rac1 signaling promotes AMPA receptor trafficking to increase synaptic strength (19,21,22). Damaging de novo mutations and ultra-rare variants in TRIO are enriched in individuals with NDDs (23)(24)(25)(26)(27)(28)(29)(30). Interestingly, nonsense variants spread throughout TRIO are enriched in individuals with SCZ (30,31), whereas pathogenic missense TRIO variants in or surrounding the GEF1 domain are associated with ASD/ID (24,28,29).…”

“…Trio in other tissues could explain the increased body weight in these mice, as well as the musculoskeletal abnormalities associated with TRIO variation in humans(23,25,27,32).…”

RNA analysis and computer‐aided facial phenotyping help to classify a novel TRIO splice site variant

“…Gain-of-function (GoF) missense variants within the spectrin repeats are associated with a more severe DD with macrocephaly (MRD 63, MIM:618825), whereas loss-of-function (LoF) missense variants in the first DH-PH (GEF1) domain and truncating variants throughout the gene are associated with a milder DD and microcephaly (MRD 44, MIM:617061) (Barbosa et al, 2020). Commonly described features in both TRIO-NDD groups comprise behavioral problems, seizures, feeding difficulties, constipation, musculoskeletal, and dental anomalies (Gazdagh et al, 2023). Dysmorphic facial features such as facial asymmetry, a tall forehead, synophrys, hypertelorism, abnormal nasal configuration, large ears, broad mouth, thin vermilion of the upper lip, and microÀ/retrognathia have been reported in individuals with TRIO-NDD (Varvagiannis et al, 2017).…”

“…Missense variants within the GEF1 domain and truncating variants leading to RAC1 inactivation were found to be associated with a milder DD and microcephaly (i.e., MRD 44 or TRIO-LoF), whereas missense variants in the spectrin repeats causing RAC1 overactivation are associated with a more severe phenotype and macrocephaly (i.e., MRD 63 or TRIO-GoF). To date, over 50 cases with TRIO-NDD have been reported and recently reviewed(Gazdagh et al, 2023;Varvagiannis et al, 2017). Interestingly, for the TRIO-LoF cases, all published nontruncating variants were located in the GEF1 subdomain DH1.…”