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

Kumar, Raman, Gardner, Alison, Bhattacharjee, Rudrarup, Agarwala, Shreya, van Eyk, Clare L. and Fry, Andrew E. ORCID: https://orcid.org/0000-0001-9778-6924 2026. Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum. Genetics in Medicine , 102734. 10.1016/j.gim.2026.102734

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Abstract

Purpose TRranscription EXport (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, mRNA 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 four TREX subunit coding genes: THOC2 and THOC6 (known disease genes), and THOC7 and ALYREF (THOC4) (candidate disease genes). Results On the background of considerable heterogeneity of 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 recognisable facial dysmorphism. We identified and studied five recurrent THOC2 variants, which give overlapping yet variable clinical presentations, including severe perinatal lethal arthrogryposis multiplex congenita (AMC). Using cells from 13 affected individuals, we show that their TREX subunit variants are generally partial loss of function (LoF), which alter protein localisation, protein stability, protein-protein interactions or delete internal or C-terminal protein functional domains. Cells from affected individuals from across all four TREX subunits studied show consistent, yet variable accumulation of DNA damage. Conclusion The molecular, cellular and in silico data with the clinical presentations define a TREX spectrum disorder due to functional variation across multiple TREX subunits.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	Full list of authors available: https://doi.org/10.1016/j.gim.2026.102734
Publisher:	Elsevier
ISSN:	1098-3600
Date of First Compliant Deposit:	28 September 2026
Last Modified:	28 Sep 2026 10:30
URI:	https://orca.cardiff.ac.uk/id/eprint/189816

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