Compromised transcription and/or export of mRNAs from the cell nucleus to the cytoplasm interferes with normal brain development and function leading to neurodevelopmental disorders as seen in patients carrying THOC2 variants, collectively called the THOC2 syndrome. THOC2 encodes for the largest subunit of the TRanscription-EXport (TREX) complex that is essential for transcription, mRNA export and protein synthesis. We have identified >65 THOC2 variants in individuals with intellectual disability (ID), speech delay, hypotonia, and microcephaly. We showed that C-terminally truncated THOC2 protein results in accumulation of R-loops (triple stranded RNA:DNA hybrid structures), increased DNA damage in neural stem cells and neurons, resulting in cognitive and sensorimotor deficits in Thoc2 ex37-38 deletion male mice (1). We hypothesise that THOC2 variants lead to R-loop accumulation and DNA damage also during early stages of human brain development, as modelled using patient-derived induced pluripotent stem cells (iPSCs). We chose three THOC2 variants from individuals with distinct clinical presentations. While all individuals carrying the THOC2 variants had ID, the p.Leu438Pro individuals had short stature and were overweight; the ex35:c.4450-2A>G individual presented ataxia, nystagmus, and clinodactyly; and the ex37-38 deletion individual had reduced weight, sensorineural hearing loss, scoliosis and abnormal myelination. Our data show that these variants have different molecular impacts. The p.Leu438Pro reduced THOC2 and other TREX subunit protein stability that was restored in the CRISPR-Cas9 corrected iPSCs. The ex35:c.4450-2A>G iPSCs showed increased DNA damage as observed by significant accumulation of γH2AX and comet assays. The ex37-38 deletion iPSCs showed accumulation of cells at G2/M cell-cycle checkpoint and premature differentiation into neurons at DIV23 but not in control iPSCs. Our data indicate that THOC2 variants that affect different domains of the THOC2 protein may have different impact on human brain development, which might explain broad variability in THOC2 syndrome clinical expressivity.