RESUMEN
Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in reduced protein stability. The splicing-defective and deletion variants result in a loss of small regions of the C-terminal THOC2 RNA binding domain (RBD). Interestingly, reduced stability of THOC2 variant proteins has a flow-on effect on the stability of the multi-protein TREX complex; specifically on the other NDD-associated THOC subunits. Our current, expanded cohort refines the core phenotype of THOC2 NDDs to language disorder and/or ID, with a variable severity, and disorders of growth. A subset of affected individuals' has severe-profound ID, persistent hypotonia and respiratory abnormalities. Further investigations to elucidate the pathophysiological basis for this severe phenotype are warranted.