Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum.
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Kumar Raman, Gardner Alison, Bhattacharjee Rudrarup, Agarwala Shreya, van Eyk Clare L, Corbett Mark A, Carroll Renee, Kroes Thessa, Ritchie Tarin, de Nys Rebekah, Mazurkiewicz Danielle, Bing Wu, Palmer Elizabeth E, Field Michael, Verseput Jolijn J A, de Vries Bert B A, Dingemans Alexander J M, Zhang Qi, Li Fuyi, Bernier Francois, Lauzon Julie, Śmigiel Robert, Ortigoza-Escobar Juan Darío, García-Cazorla Angeles, Darling Alejandra, Boerkoel Cornelius F, Huynh Stephanie, Costain Gregory, van Ham Tjakko J, Kasteleijn Esmee, van Slegtenhorst Marjon, Barakat Tahsin Stefan, Elgersma Ype, van Ierland Yvette, Veenma Danielle, Azmanov Dimitar, Weisman Allison Goetsch, Prada Carlos E, Parkash Sandhya, Rideout Andrea L, Kerstjens-Frederikse W S, Vengoechea Jaime, Schoene-Bake Jan-Christoph, Devillard Francoise, van der Smagt Jasper, Giesbertz Noor A A, Fry Andrew E, Jezkova Jana, Kampmeier Antje, Kuechler Alma, Grasshoff Ute, Bertrand Miriam, Hickey Scott E, Hunter Jesse M, Marr Mackenzie V, Dupont Juliette, Bigoni Stefania, Ferlini Alessandra, Selvatici Rita, Chatron Nicolas, Lesca Gaetan, Januel Louis, Rossi Massimiliano, Rogers Curtis, Davis Jessica M, McKenzie Fiona, Marbach Felix, Gieldon Laura, Schmidt Wolfgang M, Paquay Amina, Bittner Reginald E, Mahal Simone, Bernert Günther, Sinnerbrink Ingrid, Goodwin Linda, Cooper Sandra, Bannink Natalja, Jolly Lachlan A, McGaughran Julie, Bosman Alexis, Hernan Rebecca, Chung Wendy K, Valenzuela Irene, Cuscó Ivon, Schlüter Agatha, Pujol Aurora, Pérez-Jurado Luis Alberto, Gecz Jozef
Аннотация
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.