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, Wilhelmina 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
{"title":"Variants in TREX complex subunits (THOC2, ALYREF, THOC6, THOC7) define a neurodevelopmental disability spectrum.","authors":"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, Wilhelmina 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","doi":"10.1016/j.gim.2026.102734","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Transcription export (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, messenger RNA 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.</p><p><strong>Methods: </strong>Through international collaboration, we aggregated and assessed 40 individuals with high-impact variants across 4 TREX subunit-coding genes: THOC2 and THOC6 (known disease genes) and THOC7 and ALYREF (previously THOC4) (candidate disease genes).</p><p><strong>Results: </strong>Against the background of considerable heterogeneity in 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 recognizable facial dysmorphism. We identified and studied 5 recurrent THOC2 variants, which give overlapping yet variable clinical presentations, including severe perinatal-lethal arthrogryposis multiplex congenita. Using cells from 13 affected individuals, we show that their TREX subunit variants are generally partial loss of function, which alter protein localization, protein stability, or protein-protein interactions or delete internal or C-terminal protein functional domains. Cells from affected individuals across all 4 TREX subunits studied show consistent, yet variable, accumulation of DNA damage.</p><p><strong>Conclusion: </strong>The molecular, cellular, and in silico data, along with the clinical presentations, define a TREX spectrum disorder due to functional variation across multiple TREX subunits.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"102734"},"PeriodicalIF":6.2000,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genetics in Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.gim.2026.102734","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Transcription export (TREX) is an evolutionarily conserved multifunctional complex with essential roles in regulating transcription, messenger RNA 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 4 TREX subunit-coding genes: THOC2 and THOC6 (known disease genes) and THOC7 and ALYREF (previously THOC4) (candidate disease genes).
Results: Against the background of considerable heterogeneity in 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 recognizable facial dysmorphism. We identified and studied 5 recurrent THOC2 variants, which give overlapping yet variable clinical presentations, including severe perinatal-lethal arthrogryposis multiplex congenita. Using cells from 13 affected individuals, we show that their TREX subunit variants are generally partial loss of function, which alter protein localization, protein stability, or protein-protein interactions or delete internal or C-terminal protein functional domains. Cells from affected individuals across all 4 TREX subunits studied show consistent, yet variable, accumulation of DNA damage.
Conclusion: The molecular, cellular, and in silico data, along with the clinical presentations, define a TREX spectrum disorder due to functional variation across multiple TREX subunits.
期刊介绍：
Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health.
GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.
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