Heterogeneous genotype-phenotype relationships in TRIO-related neurodevelopmental disorder revealed by meta-analysis

The trio Rho guanine nucleotide exchange factor gene ( TRIO ) is highly expressed in the developing brain and contributes to neuronal development, specifically axon guidance, synaptogenesis, and cytoskeleton organization. Pathogenic TRIO variants are associated with a neurodevelopmental disorder with substantial phenotypic heterogeneity. Prior case series suggested genotype-phenotype associations related to variant type and location in the protein. However, these results need validation in a larger sample. The objectives of this research were to examine associations between phenotype, variant location and variant type among previously reported TRIO -related neurodevelopmental disorder cases, and identify recurrent TRIO variants. Eighty-seven previously published studies annotated in the Human Gene Mutation Database reporting at least one TRIO variant were identified. Thirty-two additional cases were ascertained from the Simons Searchlight Study. A total of 699 individual case records were reviewed. After removing redundant cases, 449 unique records remained with available genotype data, of which 228 also had available phenotype information. Along with descriptive statistics, Chi-square analysis was used to test associations between variant and head size. In a meta-analysis of reported TRIO variants, categorically-defined head size is associated with variant type (missense vs. truncating) and protein domain location. Specifically, missense variants in the spectrin-repeat domain are associated with macrocephaly whereas missense variants outside the spectrin-repeat domain and truncating variants are associated with microcephaly. The most prevalent phenotypic features were intellectual disability/developmental delay followed by autism spectrum disorder (ASD) or ASD-like behaviors. Seven recurrent TRIO variants were identified, with head size consistent across cases with the same variant. TRIO variant type and location exhibit unique phenotypic associations. This observation may help clinicians and families to anticipate neurodevelopmental outcomes. Furthermore, identified recurrent variants may serve as targets for future translational and pharmacological research.