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Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype.
Hiatt, Susan M; Trajkova, Slavica; Sebastiano, Matteo Rossi; Partridge, E Christopher; Abidi, Fatima E; Anderson, Ashlyn; Ansar, Muhammad; Antonarakis, Stylianos E; Azadi, Azadeh; Bachmann-Gagescu, Ruxandra; Bartuli, Andrea; Benech, Caroline; Berkowitz, Jennifer L; Betti, Michael J; Brusco, Alfredo; Cannon, Ashley; Caron, Giulia; Chen, Yanmin; Cochran, Meagan E; Coleman, Tanner F; Crenshaw, Molly M; Cuisset, Laurence; Curry, Cynthia J; Darvish, Hossein; Demirdas, Serwet; Descartes, Maria; Douglas, Jessica; Dyment, David A; Elloumi, Houda Zghal; Ermondi, Giuseppe; Faoucher, Marie; Farrow, Emily G; Felker, Stephanie A; Fisher, Heather; Hurst, Anna C E; Joset, Pascal; Kelly, Melissa A; Kmoch, Stanislav; Leadem, Benjamin R; Lyons, Michael J; Macchiaiolo, Marina; Magner, Martin; Mandrile, Giorgia; Mattioli, Francesca; McEown, Megan; Meadows, Sarah K; Medne, Livija; Meeks, Naomi J L; Montgomery, Sarah; Napier, Melanie P.
Afiliación
  • Hiatt SM; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: shiatt@hudsonalpha.org.
  • Trajkova S; Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
  • Sebastiano MR; Molecular Biotechnology and Health Sciences Department, Università degli Studi di Torino, via Quarello 15, 10135 Torino, Italy.
  • Partridge EC; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Abidi FE; Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • Anderson A; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Ansar M; Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland; Advanced Molecular Genetics and Genomics Disease Research and Treatment Centre, Dow University of Health Sciences, Karachi, Pakistan.
  • Antonarakis SE; Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
  • Azadi A; Obestetrics and Gynecology Department, Golestan University of Medical Sciences, Gorgan, Iran.
  • Bachmann-Gagescu R; Institute of Medical Genetics, University of Zurich, Schlieren 8952, Switzerland.
  • Bartuli A; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Benech C; Univ Brest, Inserm, EFS, UMR 1078, GGB, 29200 Brest, France.
  • Berkowitz JL; GeneDx, LLC, Gaithersburg, MD 20877, USA.
  • Betti MJ; Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Brusco A; Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
  • Cannon A; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Caron G; Molecular Biotechnology and Health Sciences Department, Università degli Studi di Torino, via Quarello 15, 10135 Torino, Italy.
  • Chen Y; GeneDx, LLC, Gaithersburg, MD 20877, USA.
  • Cochran ME; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Coleman TF; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Crenshaw MM; Pediatrics and Medical Genetics, University of Colorado, Aurora CO, USA.
  • Cuisset L; Service de Médecine Génomique des Maladies de Système et d'Organe, Département Médico-Universitaire BioPhyGen, Hôpital Cochin, APHP, Université Paris Cité, Paris, France.
  • Curry CJ; Genetic Medicine, UCSF/Fresno, Fresno, CA 93701, USA.
  • Darvish H; Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran; Nikagene Genetic Diagnostic Laboratory, Gorgan, Golestan, Iran.
  • Demirdas S; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
  • Descartes M; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Douglas J; Boston Children's Hospital, Boston, MA, USA.
  • Dyment DA; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
  • Elloumi HZ; GeneDx, LLC, Gaithersburg, MD 20877, USA.
  • Ermondi G; Molecular Biotechnology and Health Sciences Department, Università degli Studi di Torino, via Quarello 15, 10135 Torino, Italy.
  • Faoucher M; Service de Génétique Moléculaire et Génomique, CHU, Rennes 35033, France; Univ Rennes, CNRS, IGDR, UMR 6290, Rennes 35000, France.
  • Farrow EG; Children's Mercy Kansas City, Center for Pediatric Genomic Medicine, Kansas City, KS, USA.
  • Felker SA; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Fisher H; Children's Medical Center, Dallas, TX, USA.
  • Hurst ACE; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Joset P; Medical Genetics, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
  • Kelly MA; HudsonAlpha Clinical Services Lab, LLC, Huntsville, AL 35806, USA.
  • Kmoch S; Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
  • Leadem BR; GeneDx, LLC, Gaithersburg, MD 20877, USA.
  • Lyons MJ; Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • Macchiaiolo M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • Magner M; Department of Pediatrics and Inherited Metabolic Disorders, General University Hospital and First faculty of Medicine, Charles University, Prague, Czech Republic.
  • Mandrile G; Medical Genetics Unit and Thalassemia Center, San Luigi University Hospital, University of Torino, Orbassano, Italy.
  • Mattioli F; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
  • McEown M; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Meadows SK; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
  • Medne L; Childrens Hospital of Philadelphia, Philadelphia, PA, USA.
  • Meeks NJL; Section of Genetics & Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • Montgomery S; Division of Genetics and Metabolism, Children's Health, Dallas, TX, USA.
  • Napier MP; GeneDx, LLC, Gaithersburg, MD 20877, USA.
Am J Hum Genet ; 110(2): 215-227, 2023 02 02.
Article en En | MEDLINE | ID: mdl-36586412
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastornos del Neurodesarrollo / Discapacidad Intelectual / Malformaciones del Sistema Nervioso Tipo de estudio: Prognostic_studies Límite: Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastornos del Neurodesarrollo / Discapacidad Intelectual / Malformaciones del Sistema Nervioso Tipo de estudio: Prognostic_studies Límite: Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos