Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum

PURPOSE: Transcription export (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, messenger RNA export, genome stability, cell differentiation, and survival. We aimed to determine if variation in the TREX subunits, in addition to THOC2 and THOC6 genes, caused neurodevelopmental disorders. METHODS: Through international collaboration, we aggregated and assessed 40 individuals with high-impact variants across 4 TREX subunit-coding genes: THOC2 and THOC6 (known disease genes) and THOC7 and ALYREF (previously THOC4) (candidate disease genes). RESULTS: Against the background of considerable heterogeneity in neurodevelopmental and clinical outcomes, we noted that all TREX subunit variants impact cognitive functioning and development, speech, and the respiratory systems, as well as result in recognizable facial dysmorphism. We identified and studied 5 recurrent THOC2 variants, which give overlapping yet variable clinical presentations, including severe perinatal-lethal arthrogryposis multiplex congenita. Using cells from 13 affected individuals, we show that their TREX subunit variants are generally partial loss of function, which alter protein localization, protein stability, or protein-protein interactions or delete internal or C-terminal protein functional domains. Cells from affected individuals across all 4 TREX subunits studied show consistent, yet variable, accumulation of DNA damage. CONCLUSION: The molecular, cellular, and in silico data, along with the clinical presentations, define a TREX spectrum disorder due to functional variation across multiple TREX subunits.