Raman Kumar, Alison Gardner, Rudrarup Bhattacharjee, Shreya Agarwala, Clare L van Eyk, Mark A Corbett, Renee Carroll, Thessa Kroes, Tarin Ritchie, Rebekah de Nys, Danielle Mazurkiewicz, Wu Bing, Elizabeth E Palmer, Michael Field, Jolijn J A Verseput, Bert B A de Vries, Alexander J M Dingemans, Qi Zhang, Fuyi Li, Francois Bernier, Julie Lauzon, Robert Śmigiel, Juan Darío Ortigoza-Escobar, Angeles García-Cazorla, Alejandra Darling, Cornelius F Boerkoel, Stephanie Huynh, Gregory Costain, Tjakko J van Ham, Esmee Kasteleijn, Marjon van Slegtenhorst, Tahsin Stefan Barakat, Ype Elgersma, Yvette van Ierland, Danielle Veenma, Dimitar Azmanov, Allison Goetsch Weisman, Carlos E Prada, Sandhya Parkash, Andrea L Rideout, W S Kerstjens-Frederikse, Jaime Vengoechea, Jan-Christoph Schoene-Bake, Francoise Devillard, Jasper van der Smagt, Noor A A Giesbertz, Andrew E Fry, Jana Jezkova, Antje Kampmeier, Alma Kuechler, Ute Grasshoff, Miriam Bertrand, Scott E Hickey, Jesse M Hunter, Mackenzie V Marr, Juliette Dupont, Stefania Bigoni, Alessandra Ferlini, Rita Selvatici, Nicolas Chatron, Gaetan Lesca, Louis Januel, Massimiliano Rossi, Curtis Rogers, Jessica M Davis, Fiona McKenzie, Felix Marbach, Laura Gieldon, Wolfgang M Schmidt, Amina Paquay, Reginald E Bittner, Simone Mahal, Günther Bernert, Ingrid Sinnerbrink, Linda Goodwin, Sandra Cooper, Natalja Bannink, Lachlan A Jolly, Julie McGaughran, Alexis Bosman, Rebecca Hernan, Wendy K Chung, Irene Valenzuela, Ivon Cuscó, Agatha Schlüter, Aurora Pujol, Luis Alberto Pérez-Jurado, Jozef Gecz
The molecular, cellular and in silico data with the clinical presentations define a TREX spectrum disorder due to functional variation across multiple TREX subunits.
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.