부산대학교 도서관

Keywords ZMYM3; X-linked intellectual disability; neurodevelopmental disorder; transcriptional coregulators; chromatin modifiers Summary Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene. Author Affiliation: (1) HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA (2) Department of Medical Sciences, University of Torino, 10126 Torino, Italy (3) Molecular Biotechnology and Health Sciences Department, Università degli Studi di Torino, via Quarello 15, 10135 Torino, Italy (4) Greenwood Genetic Center, Greenwood, SC 29646, USA (5) Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland (6) Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland (7) Obestetrics and Gynecology Department, Golestan University of Medical Sciences, Gorgan, Iran (8) Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland (9) Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy (10) Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200 Brest, France (11) GeneDx, LLC, Gaithersburg, MD 20877, USA (12) Vanderbilt University Medical Center, Nashville, TN 37232, USA (13) Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA (14) Pediatrics and Medical Genetics, University of Colorado, Aurora CO, USA (15) Service de Médecine Génomique des Maladies de Système et d'Organe, Département Médico-Universitaire BioPhyGen, Hôpital Cochin, APHP, Université Paris Cité, Paris, France (16) Genetic Medicine, UCSF/Fresno, Fresno, CA 93701, USA (17) Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran (18) Nikagene Genetic Diagnostic Laboratory, Gorgan, Golestan, Iran (19) Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands (20) Boston Children's Hospital, Boston, MA, USA (21) Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada (22) Service de Génétique Moléculaire et Génomique, CHU, Rennes 35033, France (23) Univ Rennes, CNRS, IGDR, UMR 6290, Rennes 35000, France (24) Children's Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, KS, USA (25) Children's Medical Center, Dallas, TX, USA (26) Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland (27) HudsonAlpha Clinical Services Lab, LLC, Huntsville, AL 35806, USA (28) Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (29) Department of Pediatrics and Inherited Metabolic Disorders, General University Hospital and First faculty of Medicine, Charles University, Prague, Czech Republic (30) Medical Genetics Unit and Thalassemia Center, San Luigi University Hospital, University of Torino, Orbassano, Italy (31) Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland (32) Childrens Hospital of Philadelphia, Philadelphia, PA, USA (33) Section of Genetics & Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA (34) Division of Genetics and Metabolism, Children's Health, Dallas, TX, USA (35) Pathology & Laboratory Medicine, Genomic Medicine, Neurological and Pediatrics Institutes, Cleveland Clinic, Cleveland, OH, USA (36) Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, CHU Hôpital Sud, Rennes, France (37) Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT 84112, USA (38) University Children's Hospital Zurich, University of Zurich, Zurich 8032, Switzerland (39) Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France (40) Centre de Référence Déficiences Intellectuelles de causes rares, Brest, France (41) Division of Genetics, Children's Mercy Kansas City, Kansas City, MO, USA (42) Genetics and Metabolism, Arkansas Children's Hospital, Little Rock, AR 72202, USA (43) Department of Pediatrics, Division of Genetics and Metabolism, University of Texas Southwestern Medical Center, Dallas, TX, USA (44) Department of Endocrinology and Genetics, University Clinic for Children's Diseases, Medical Faculty, University Sv. Kiril i Metodij, Skopje, Republic of Macedonia (45) Amsterdam University Medical Centers, Department of Clinical Genetics, Amsterdam, the Netherlands (46) Department of Human Genetics, Amsterdam University Medical Centers, VU University Amsterdam, Amsterdam, The Netherlands (47) Amsterdam Neuroscience, Amsterdam, The Netherlands (48) Harvard Medical School, Boston, MA 02115, USA (49) Advanced Molecular Genetics and Genomics Disease Research and Treatment Centre, Dow University of Health Sciences, Karachi, Pakistan * Corresponding author Article History: Received 1 September 2022; Accepted 8 December 2022 (miscellaneous) Published: December 30, 2022 Byline: Susan M. Hiatt [shiatt@hudsonalpha.org] (1,*), Slavica Trajkova (2), Matteo Rossi Sebastiano (3), E. Christopher Partridge (1), Fatima E. Abidi (4), Ashlyn Anderson (1), Muhammad Ansar (5,49), Stylianos E. Antonarakis (6), Azadeh Azadi (7), Ruxandra Bachmann-Gagescu (8), Andrea Bartuli (9), Caroline Benech (10), Jennifer L. Berkowitz (11), Michael J. Betti (12), Alfredo Brusco (2), Ashley Cannon (13), Giulia Caron (3), Yanmin Chen (11), Meagan E. Cochran (1), Tanner F. Coleman (1), Molly M. Crenshaw (14), Laurence Cuisset (15), Cynthia J. Curry (16), Hossein Darvish (17,18), Serwet Demirdas (19), Maria Descartes (13), Jessica Douglas (20), David A. Dyment (21), Houda Zghal Elloumi (11), Giuseppe Ermondi (3), Marie Faoucher (22,23), Emily G. Farrow (24), Stephanie A. Felker (1), Heather Fisher (25), Anna C.E. Hurst (13), Pascal Joset (26), Melissa A. Kelly (27), Stanislav Kmoch (28), Benjamin R. Leadem (11), Michael J. Lyons (4), Marina Macchiaiolo (9), Martin Magner (29), Giorgia Mandrile (30), Francesca Mattioli (31), Megan McEown (1), Sarah K. Meadows (1), Livija Medne (32), Naomi J.L. Meeks (33), Sarah Montgomery (34), Melanie P. Napier (11), Marvin Natowicz (35), Kimberly M. Newberry (1), Marcello Niceta (9), Lenka Noskova (28), Catherine B. Nowak (20), Amanda G. Noyes (11), Matthew Osmond (21), Eloise J. Prijoles (4), Jada Pugh (1), Verdiana Pullano (2), Chloé Quélin (36), Simin Rahimi-Aliabadi (37), Anita Rauch (8,38), Sylvia Redon (10,39,40), Alexandre Reymond (31), Caitlin R. Schwager (41), Elizabeth A. Sellars (42), Angela E. Scheuerle (43), Elena Shukarova-Angelovska (44), Cara Skraban (32), Elliot Stolerman (4), Bonnie R. Sullivan (41), Marco Tartaglia (9), Isabelle Thiffault (24), Kevin Uguen (10,39,40), Luis A. Umaña (43), Yolande van Bever (19), Saskia N. van der Crabben (45), Marjon A. van Slegtenhorst (19), Quinten Waisfisz (46,47), Camerun Washington (4), Lance H. Rodan (20,48), Richard M. Myers (1), Gregory M. Cooper [gcooper@hudsonalpha.org] (1,**)