부산대학교 도서관

TUDP Study Group Keywords Neurodevelopment; global developmental delay; brain malformation; epilepsy; macrocephaly; intellectual disability; hypotonia; gastrointestinal issues; FBXW7; F-box protein Summary Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7. Author Affiliation: (1) Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia (2) Department of Paediatrics, University of Melbourne, Melbourne, VIC 3052, Australia (3) Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (4) Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (5) Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada (6) Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6525, the Netherlands (7) Structural Biology and Bioinformatics, Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC 3052, Australia (8) Australia Cancer Research Funding Facility for Innovative Cancer Drug Discovery, Bio21 Institute, University of Melbourne, Melbourne, VIC 3052, Australia (9) Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia (10) Division of Neurology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (11) Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (12) The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (13) Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (14) Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada (15) Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States (16) Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States (17) Department of Pediatrics, Harvard Medical School, Boston, MA 02115, United States (18) Cancer and Blood Disorders Center, Boston Children's Hospital, Boston, MA 02115, United States (19) Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, United States (20) Broad Institute of MIT and Harvard, Cambridge, MA 02115, United States (21) Department of Child and Adolescent Psychiatry, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States (22) Department of Clinical Genetics, Children's Health Ireland at Temple Street, Rotunda, Dublin D01 XD99, Ireland (23) Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, United States (24) Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, United States (25) Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, United States (26) Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States (27) Otolaryngology--Head and Neck Surgery (Ear, Nose, and Throat), Mayo Clinic, Rochester, MN 55905, United States (28) Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, United States (29) Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, United States (30) Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, United States (31) Institute for Genomic Medicine and Precision Genomics Laboratory, Columbia University Irving Medical Center, New York, NYk, 10032, United States (32) Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada (33) Division of Pediatrics, University of South Florida, Tampa, FL 33620, United States (34) Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo 6997801, Israel (35) Institute of Rare Diseases, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel (36) Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel (37) The Genomic Unit, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel (38) The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Ramat Gan 52621, Israel (39) Centre Pluridisciplinaire de Diagnostic PréNatal, Pôle Mère Enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, Nouvelle-Aquitaine 33401, France (40) Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, Bourgogne-Franche-Comté 21000, France (41) INSERM U1231, Laboratoire de Neurosciences Cognitives, UMR 1231, Genetic of Development Anomalies, University of Burgundy, Dijon, Bourgogne-Franche-Comté 21078 France (42) Reference Center for Genetic, Complex, and Rare Skin Disorders, Department of Pediatric Dermatology, Bordeaux University Hospital, Bordeaux, Nouvelle-Aquitaine 33000, France (43) Laboratoire de Génétique Chromosomique et Moléculaire, Pôle de Biologie, Centre Hospitalier Universitaire de Dijon, Dijon, Bourgogne-Franche-Comté 21000 France (44) Neurology Department, New York University Langone Medical Center, New York, NY 10016, United States (45) Department of Human Genetics, Emory Healthcare, Atlanta, GA 30322, United States (46) Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, 30322, United States (47) Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, 30322, United States (48) Indiana University School of Medicine, Indianapolis, Indiana 46202, United States (49) Indiana University Health Physicians, Indiana University, Indianapolis, Indiana 46202, United States (50) Reference Center for Developmental Disorders, Department of Medical Genetics, Arnaud de Villeneuve Hospital, Montpellier University Hospital, Montpellier, Occitanie 34295, France (51) Inserm UMR 1231, Genetics of Developmental Anomalies, University of Bourgogne, University Hospital Federation, Translational Medicine in Development Disorders, Dijon, Bourgogne-Franche-Comté 21078, France (52) New South Wales Health Pathology East Laboratory, Prince of Wales Private Hospital, Sydney, NSW 2031, Australia (53) Neuroscience Research Australia, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia (54) Centre for Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales 2031, Australia (55) School of Women's and Children's Health, University of New South Wales Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia (56) Newcastle Genetics of Learning Disability Service, Hunter Genetics, Newcastle, New South Wales 2298, Australia (57) Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States (58) Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC 3084, Australia (59) Department of Pediatrics, University of Washington, Seattle, WA 98195, United States (60) GeneDx, Gaithersburg, MD 20877, United States (61) Medical Genetic Services, The Thorax Institute, INSERM, Centre National de la Recherche Scientifique, University Hospital of Nantes, Nantes, Pays de la Loire 44007, France (62) Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, Illkirch-Graffenstaden 67000, France (63) Institute of Genetics and Molecular and Cellular Biology, INSERM U964, Centre National de la Recherche Scientifique, UMR 7104, University of Strasbourg, Illkirch-Graffenstaden, Grand Est 67400, France (64) Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Chubu 467-8601, Japan (65) Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Chubu 464-860, Japan (66) Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Chubu 441-8570, Japan (67) Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, Chubu 467-8601, Japan (68) Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON L5B 1B8, Canada (69) Victorian Clinical Genetics Services, Melbourne, VIC 3052, Australia (70) Population Health and Immunity Division, The Walter and Eliza Hall Institute for Medical Research, Melbourne, VIC 3052, Australia (71) Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia (72) deCODE Genetics, Amgen, Reykjavik 101, Iceland (73) Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland (74) Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik 101, Iceland (75) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, United States (76) Department of Medical Imaging, The Royal Children's Hospital, Melbourne, VIC 3052, Australia (77) Telethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy (78) Department of Precision Medicine, University of Campania 'Luigi Vanvitelli,' Naples 80138, Italy (79) Department of Pediatrics, Azienda Socio Sanitaria Territoriale, Lariana Sant'Anna Hospital, San Fermo Della Battaglia, Como 22042, Italy (80) Department of Neurosciences, Rehabilitation, Opthalmology, Genetics, and Maternal and Child Health, University of Genoa, Genoa, Liguria 16126, Italy (81) Istituto di Ricovero e Cura a Carattere Scientifico Giannina Gaslini Institute, Genoa, Liguria 16147, Italy (82) Tasmanian Clinical Genetics Services, Royal Hobart Hospital, Hobart, Tasmania 7000, Australia (83) Department of Human Genetics, Amsterdam University Medical Centers, Vrije Universiteit Medical Center Amsterdam, Amsterdam, the Netherlands (84) Department of Biochemistry, University of Cambridge, Cambridge, England CB2 1GA, United Kingdom * Corresponding author Article History: Received 28 October 2021; Accepted 28 February 2022 (miscellaneous) Published: April 7, 2022 Byline: Sarah E.M. Stephenson (1,2), Gregory Costain (3,4,5), Laura E.R. Blok (6), Michael A. Silk (7,8,9), Thanh Binh Nguyen (7,8,9), Xiaomin Dong (1), Dana E. Alhuzaimi (1), James J. Dowling (10,11), Susan Walker (11,12), Kimberly Amburgey (5,10), Robin Z. Hayeems (13,14), Lance H. Rodan (15,16), Marc A. Schwartz (17,18,19,20), Jonathan Picker (15,21), Sally A. Lynch (22), Aditi Gupta (23,24), Kristen J. Rasmussen (25), Lisa A. Schimmenti (26,27,28), Eric W. Klee (23,24,25,26), Zhiyv Niu (25,26), Katherine E. Agre (26), Ilana Chilton (29), Wendy K. Chung (29,30), Anya Revah-Politi (31), P.Y. Billie Au (32), Christopher Griffith (33), Melissa Racobaldo (33), Annick Raas-Rothschild (34,35), Bruria Ben Zeev (34,36), Ortal Barel (37,38), Sebastien Moutton (39,40,41), Fanny Morice-Picard (42), Virginie Carmignac (41), Jenny Cornaton (40), Nathalie Marle (43), Orrin Devinsky (44), Chandler Stimach (45), Stephanie Burns Wechsler (46,47), Bryan E. Hainline (48,49), Katie Sapp (48,49), Marjolaine Willems (50), Ange-line Bruel (51), Kerith-Rae Dias (52,53), Carey-Anne Evans (52,53), Tony Roscioli (52,53,54), Rani Sachdev (54,55), Suzanna E.L. Temple (52,53,54), Ying Zhu (52,56), Joshua J. Baker (57), Ingrid E. Scheffer (1,2,58), Fiona J. Gardiner (58), Amy L. Schneider (58), Alison M. Muir (59), Heather C. Mefford (59), Amy Crunk (60), Elizabeth M. Heise (60), Francisca Millan (60), Kristin G. Monaghan (60), Richard Person (60), Lindsay Rhodes (60), Sarah Richards (60), Ingrid M. Wentzensen (60), Benjamin Cogné (61), Bertrand Isidor (61), Mathilde Nizon (61), Marie Vincent (61), Thomas Besnard (61), Amelie Piton (62,63), Carlo Marcelis (6), Kohji Kato (64,65), Norihisa Koyama (66), Tomoo Ogi (65,67), Elaine Suk-Ying Goh (68), Christopher Richmond (69), David J. Amor (1,2,69), Jessica O. Boyce (1,2), Angela T. Morgan (1,2), Michael S. Hildebrand (1,58), Antony Kaspi (70,71), Melanie Bahlo (70,71), Rún Friðriksdóttir (72), Hildigunnur Katrínardóttir (72), Patrick Sulem (72), Kári Stefánsson (72,73), Hans Tómas Björnsson (73,74,75), Simone Mandelstam (2,76), Manuela Morleo (77,78), Milena Mariani (79), Marcello Scala (80,81), Andrea Accogli (80,81), Annalaura Torella (77), Valeria Capra (81), Mathew Wallis (82), Sandra Jansen (83), Quinten Waisfisz (83), Hugoline de Haan (83), Simon Sadedin (1,69), Sze Chern Lim (1,69), Susan M. White (1,2,69), David B. Ascher (7,8,9,84), Annette Schenck (6), Paul J. Lockhart (1,2), John Christodoulou (1,2,69), Tiong Yang Tan [tiong.tan@vcgs.org.au] (1,2,69,*)