Proper transcription and export of mature RNA to cytoplasm is regulated by a highly conserved multi-subunit TRanscription-EXport (TREX) complex. To better understand the fundamental roles of TREX biology, we are taking advantage of naturally-occurring variation in its subunits from >60 individuals with neurodevelopmental disabilities (NDD). Through international collaboration, we have aggregated individuals with pathogenic or predicted to be deleterious variants across THOC2, THOC4/ALYREF, THOC6 and THOC7 subunits. Among these, THOC4/ALYREF and THOC7 are novel NDD genes. Neurodevelopmental outcomes of affected individuals varied broadly and included intellectual disability, speech delay, hypotonia, microcephaly and cerebral palsy. THOC2 affected individuals also presented with a recognisable face. The male mice of the X-chromosome linked Thoc2 gene, expressing a C-terminally truncated THOC2 protein (Bhattacharjee et al 2024 Nature Communications 15:1210) accumulated triple stranded RNA:DNA hybrids (R-loops) and showed increased DNA damage in replicating (neural stem) as well as postmitotic (cortical neurons) cells. The mice showed learning and memory and sensorimotor deficits. Using patient skin fibroblasts, we generated iPSCs for three THOC2 variants from individuals with different clinical severity. The p.Leu438Pro iPSCs showed reduced stability of THOC2 and other TREX subunits, which was restored in the CRISPR/Cas9 variant-corrected iPSCs. The other two variants, c.4450-2A>G (exon 35-36 skipping; Asp1484-Lys1559del) and exon 37-38 deletion caused in frame C-terminal deletions. We detected significantly increased DNA damage in primary cells of patients with variants in TREX subunits, THOC2, ALYREF, THOC6 and THOC7. THOC6 variants caused protein mis-localisation and loss of interaction with the other TREX components, and THOC7 variant caused reduced protein stability. While different variants of TREX subunits affected their proteins and function differently, they largely converge on R-loop mal-resolution and consequent DNA damage accumulation in transcriptionally active, proliferative as well as in postmitotic cells, i.e. neurons; if this contributes to the disease pathology is the major focus of our ongoing studies.