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For Peer Review Human Mutation Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery Journal:For Human Peer Mutation Review Manuscript ID Draft Wiley - Manuscript type: Research Article Date Submitted by the Author: n/a Complete List of Authors: Gecz, Jozef; University of Adelaide, Adelaide Medical School and the Robinson Research Institute Sharma , Raman; The University of Adelaide, Adelaide Medical School and the Robinson Research Institute Gardner, Alison; The University of Adelaide, Adelaide Medical School and the Robinson Research Institute Homan, Claire; The University of Adelaide; Robinson Research Institute Douglas, Evelyn; Genetics and Molecular Pathology, SA Pathology Mefford, Heather; Division of Genetic Medicine, Department of Pediatrics, University of Washington Wieczorek, Dagmar; Universitatsklinikum Dusseldorf, Institut für Humangenetik; Heinrich-Heine-Universitat Dusseldorf, Institut für Humangenetik Lüdecke, Hermann-Josef; Heinrich-Heine-University, Medical Faculty, Institute of Human Genetics, Düsseldorf, Germany and Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen Stark, Zornitza; Murdoch Children’s Research Institute, Victorian Clinical Genetics Services Sadedin, Simon; Murdoch Children's Research Institute and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard Nowak, Catherine Bearce; Boston Children's Hospital douglas, Jessica; Boston Children's Hospital Parsons, Gretchen; Spectrum Health Medical Genetics Mark, Paul; Spectrum Health Medical Genetics Loidi, Lourdes; Fundación Pública Galega de Medicina Xenómica, Hospital Clínico Universitario de Santiago de, Compostela Herman, Gail; Nationwide Children’s Hospital and The Ohio State University Mihalic Mosher, Theresa; Nationwide Children’s Hospital and The Ohio State University Gillespie, Meredith; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa Brady, Lauren; Department of Pediatrics, McMaster University Medical Centre Tarnopolsky, Mark; McMaster University Medical Center, Dept. Pediatrics and Medicine Madrigal, Irene; Fundación Pública Galega de Medicina Xenómica, Hospital John Wiley & Sons, Inc. Page 1 of 67 Human Mutation 1 2 3 4 Clínico Universitario de Santiago de Compostela Eiris, Jesus; Unidad de Neurología Pediátrica, Departamento de Pediatría, 5 Hospital Clínico Universitario de Santiago de Compostela 6 Domenech Salgado, Laura; Centre de Regulacio Genomica; Universitat 7 Pompeu Fabra 8 Rabionet, Raquel; FUNDACIÓ PRIVADA PER A LA RECERCA I LA DOCÈNCIA 9 SANT JOAN DE DÉU , departament de genètica, microbiologia i estadística 10 de la UB; Universitat de Barcelona Facultat de Biologia, Strom, Tim; Helmholtz Zentrum München, Institute of Human Genetics 11 Ishihara, Naoko; Department of Pediatrics, Fujita Health University School 12 of Medicine 13 Inagaki, Hidehito; Fujita Health University, ICMS 14 Kurahashi, Hiroki; Fujita Health University, Institute for Comprehensive 15 Medical Science, Division of Molecular Genetics 16 Dudding, Tracy; Hunter New England Local Health District, Hunter Genetics ; University of Newcastle, 17 Palmer , Emma; Genetics of Learning Disability Service, Hunter Genetics 18 Field, Michael; Hunter Genetics, The GOLD Service 19 For Peer Review XLID, THOC2, mRNA export, protein stability, partial loss-of-function 20 Key Words: 21 variants 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Human Mutation Page 2 of 67 1 2 3 RESEARCH ARTICLE 4 5 Severe neurocognitive and growth disorders due to variation in THOC2, an essential 6 component of nuclear mRNA export machinery 7 8 9 1 1 1 2 3 10 Raman Kumar , Alison Gardner , Claire Homan , Evelyn Douglas , Heather Mefford , 4 4 5 6 11 Dagmar Wieczorek , Hermann-Josef Lüdecke , Zornitza Stark , Simon Sadedin , The Broad 7 8 8 9 9 12 CMG , Catherine Bearce Nowak , Jessica Douglas , Gretchen Parsons , Paul Mark , Lourdes 13 Loidi10, Gail Herman11, Theresa Mihalic Mosher11, Meredith K Gillespie12, Lauren Brady13, 14 Mark Tarnopolsky13, Irene Madrigal14, Jesús Eiris15, Laura Domenech Salgado16, Raquel 15 Rabionet16, Tim M Strom17, Naoko Ishihara18, Hidehito Inagaki19, Hiroki Kurahashi19, 16 Tracy Dudding-Byth20,21, Elizabeth Palmer20,22, Michael Field20, Jozef Gecz1,23* 17 18 19 1Adelaide Medical SchoolFor and thePeer Robinson ResearchReview Institute, The University of Adelaide, 20 Adelaide, SA5000, Australia; 2Genetics and Molecular Pathology, SA Pathology, Adelaide, 21 SA5000, Australia; 3Division of Genetic Medicine, Department of Pediatrics, University of 22 4 23 Washington & Seattle Children’s Hospital, Seattle, Washington, USA; Heinrich-Heine- 24 University, Medical Faculty, Institute of Human Genetics, Düsseldorf, Germany and Institut 25 für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, 5 26 Germany; Murdoch Children's Research Institute and 27 Department of Pediatrics, University of Melbourne, Melbourne, Australia; 6Murdoch 28 Children's Research Institute and 29 Program in Medical and Population Genetics, Broad Institute of MIT and 30 Harvard, Cambridge, Massachusetts, USA; 7Broad’s Center for Mendelian Genomics, 31 Cambridge, Massachusetts, USA; 8Boston Children's Hospital, Longwood Avenue, Boston, 32 MA, USA; 9Spectrum Health Medical Genetics, Grand Rapids, MI, USA; 10Fundación 33 Pública Galega de Medicina Xenómica, Hospital Clínico Universitario de Santiago de, 34 11 35 Compostela. Santiago de Compostela, Spain; Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, USA; 12Children's Hospital of Eastern Ontario Research 36 13 37 Institute, University of Ottawa, Ottawa, Canada; Department of Pediatrics, McMaster 14 38 University Medical Centre, Hamilton, Canada; Fundación Pública Galega de Medicina 39 Xenómica, Hospital Clínico Universitario de Santiago de Compostela, Santiago de 40 Compostela, Spain; 15Unidad de Neurología Pediátrica, Departamento de Pediatría, Hospital 41 Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain; 16Centre 42 for Genomic Regulation (CRG), Universitat Pompeu Fabra and CIBERESP, Barcelona 43 Institute for Science and Technology, Barcelona, Spain; 17Institut für Humangenetik, 44 Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany; 18Department of 45 Pediatrics, Fujita Health University School of Medicine, Japan; 19Division of Molecular 46 Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Japan; 47 20Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, Australia; 48 21 22 49 University of Newcastle, Australia Grow-Up-Well Priority Research Center; School of 50 Women’s and Children’s Health, University of New South Wales, Randwick, NSW 2031, 23 51 Australia; Healthy Mothers, Babies and Children, South Australian Health and Medical 52 Research Institute, Adelaide, SA 5000, Australia. 53 54 *Correspondence: Jozef Gecz, 1School of Medicine, The Robinson Research Institute, The 55 University of Adelaide, North Adelaide, SA5005, Australia. E-mail: 56 [email protected] 57 58 1 59 60 John Wiley & Sons, Inc. Page 3 of 67 Human Mutation 1 2 3 Abstract 4 5 Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal 6 7 development and differentiation. TREX subunit variants cause perturbed mRNA export from 8 9 the cell nucleus to the cytoplasm and lead to neurodevelopmental disorders (NDDs). Our 10 11 previous work implicated the THOC2 gene on the X-chromosome in intellectual disability 12 13 14 (ID). Borderline to severe ID with speech delay, behavioural problems, short stature, elevated 15 16 BMI and truncal obesity in adulthood were observed. We now report an additional six 17 18 affected individuals from five unrelated families with pathogenic or likely pathogenic 19 For Peer Review 20 variants in THOC2, two de novo and three maternally-inherited, extending the genotypic and 21 22 phenotypic spectrum. These comprise three rare missense THOC2 variants that affect 23 24 evolutionarily conserved amino acid residues and reduce protein stability and affected males 25 26 27 from two families with canonical splice-site THOC2 variants that result in C-terminally 28 29 truncated THOC2 proteins. We present detailed clinical assessment and functional studies on 30 31 a de novo variant in a female with an epileptic encephalopathy and discuss an additional four 32 33 families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe 34 35 neurocognitive features, including movement and seizure disorders were observed in this 36 37 expanded cohort. Taken together, our data significantly expand existing evidence showing 38 39 40 that even subtle alterations to the canonical molecular pathways such as mRNA export, 41 42 otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans. 43 44 45 46 47 48 KEY WORDS 49 50 XLID; THOC2; mRNA export; protein stability; partial loss-of-function variants 51 52 53 54 55 56 57 58 2 59 60 John Wiley & Sons, Inc. Human Mutation Page 4 of 67 1 2 3 INTRODUCTION 4 5 Intellectual disability (ID), characterized by substantial limitations in both intellectual 6 7 functioning and adaptive behaviour, affects 1-3% of the population starting before the age of 8 9 18 years and has significant impact on individuals, families and communities (Vissers, et al., 10 11 2016). Individuals
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