den Hoed J 1 , de Boer E 2 , Voisin N 3 , Dingemans AJM 2 , Guex N 4 , Wiel L 5 Show all authors , Nellaker C 6 , Amudhavalli SM 7 , Banka S 8 , Bena FS 9 , Ben-Zeev B 10 , Bonagura VR 11 , Bruel AL 12 , Brunet T 13 , Brunner HG 14 , Chew HB 15 , Chrast J 3 , Cimbalistienė L 16 , Coon H 17 , DDD Study 18 , Délot EC 19 , Démurger F 20 , Denommé-Pichon AS 12 , Depienne C 21 , Donnai D 8 , Dyment DA 22 , Elpeleg O 23 , Faivre L 24 , Gilissen C 25 , Granger L 26 , Haber B 27 , Hachiya Y 28 , Abedi YH 29 , Hanebeck J 27 , Hehir-Kwa JY 30 , Horist B 31 , Itai T 32 , Jackson A 33 , Jewell R 34 , Jones KL 35 , Joss S 36 , Kashii H 28 , Kato M 37 , Kattentidt-Mouravieva AA 38 , Kok F 39 , Kotzaeridou U 27 , Krishnamurthy V 31 , Kučinskas V 16 , Kuechler A 21 , Lavillaureix A 40 , Liu P 41 , Manwaring L 42 , Matsumoto N 32 , Mazel B 43 , McWalter K 44 , Meiner V 23 , Mikati MA 45 , Miyatake S 32 , Mizuguchi T 32 , Moey LH 46 , Mohammed S 47 , Mor-Shaked H 23 , Mountford H 48 , Newbury-Ecob R 49 , Odent S 40 , Orec L 27 , Osmond M 22 , Palculict TB 44 , Parker M 50 , Petersen AK 26 , Pfundt R 51 , Preikšaitienė E 16 , Radtke K 52 , Ranza E 53 , Rosenfeld JA 54 , Santiago-Sim T 44 , Schwager C 7 , Sinnema M 55 , Snijders Blok L 56 , Spillmann RC 57 , Stegmann APA 58 , Thiffault I 59 , Tran L 45 , Vaknin-Dembinsky A 60 , Vedovato-Dos-Santos JH 61 , Schrier Vergano SA 62 , Vilain E 19 , Vitobello A 12 , Wagner M 63 , Waheeb A 64 , Willing M 42 , Zuccarelli B 65 , Kini U 66 , Newbury DF 48 , Kleefstra T 2 , Reymond A 3 , Fisher SE 67 , Vissers LELM 2

Affiliations 

  • 1 Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6500 AH Nijmegen, the Netherlands; International Max Planck Research School for Language Sciences, Max Planck Institute for Psycholinguistics, 6500 AH Nijmegen, the Netherlands
  • 2 Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands
  • 3 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
  • 4 Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Bioinformatics Competence Center, University of Lausanne, 1015 Lausanne, Switzerland
  • 5 Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Center for Molecular and Biomolecular Informatics of the Radboudumc, 6500 HB Nijmegen, the Netherlands
  • 6 Nuffield Department of Women's and Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK; Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Oxford OX3 7DQ, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK
  • 7 University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA; Department of Pediatrics, Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO 64108, USA
  • 8 Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester M13 9WL, UK
  • 9 Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland
  • 10 Edmomd and Lilly Safra Pediatric Hospital, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel
  • 11 Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; Pediatrics and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
  • 12 UMR1231-Inserm, Génétique des Anomalies du développement, Université de Bourgogne Franche-Comté, 21070 Dijon, France; Laboratoire de Génétique chromosomique et moléculaire, UF6254 Innovation en diagnostic génomique des maladies rares, Centre Hospitalier Universitaire de Dijon, 21070 Dijon, France
  • 13 Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany
  • 14 Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands; Maastricht University Medical Center, Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, and MHeNS School for Mental health and Neuroscience, PO Box 5800, 6202AZ Maastricht, the Netherlands
  • 15 Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia
  • 16 Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania
  • 17 Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
  • 18 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
  • 19 Center for Genetic Medicine Research, Children's National Hospital, Children's Research Institute and Department of Genomics and Precision Medicine, George Washington University, Washington, DC 20010, USA
  • 20 Department of clinical genetics, Vannes hospital, 56017 Vannes, France
  • 21 Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
  • 22 Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada
  • 23 Department of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel
  • 24 UMR1231-Inserm, Génétique des Anomalies du développement, Université de Bourgogne Franche-Comté, 21070 Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, 21079 Dijon, France
  • 25 Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands
  • 26 Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA
  • 27 Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
  • 28 Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo 183-0042, Japan
  • 29 Division of Allergy and Immunology, Northwell Health, Great Neck, NY 11021, USA; Departments of Medicine and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
  • 30 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands
  • 31 Pediatrics & Genetics, Alpharetta, GA 30005, USA
  • 32 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
  • 33 Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
  • 34 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK
  • 35 Division of Medical Genetics & Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA; Department of Pediatrics, Eastern Virginia Medical School, Norfolk, VA 23507, USA
  • 36 West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
  • 37 Department of Pediatrics, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8666, Japan
  • 38 Zuidwester, 3240AA Middelharnis, the Netherlands
  • 39 Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil; University of Sao Paulo, School of Medicine, Sao Paulo, SP 01246-903, Brazil
  • 40 CHU Rennes, Univ Rennes, CNRS, IGDR, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 35033 Rennes, France
  • 41 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA
  • 42 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA
  • 43 Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France
  • 44 GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA
  • 45 Division of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, USA
  • 46 Department of Genetics, Penang General Hospital, Jalan Residensi, 10990 Georgetown, Penang, Malaysia
  • 47 Clinical Genetics, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK
  • 48 Department of Biological and Medical Sciences, Headington Campus, Oxford Brookes University, Oxford OX3 0BP, UK
  • 49 Clinical Genetics, St Michael's Hospital Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8EG, UK
  • 50 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S5 7AU, UK
  • 51 Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands
  • 52 Clinical Genomics Department, Ambry Genetics, Aliso Viejo, CA 92656, USA
  • 53 Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland
  • 54 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
  • 55 Department of Clinical Genetics, Maastricht University Medical Center+, azM, 6202 AZ Maastricht, the Netherlands; Department of Genetics and Cell Biology, Faculty of Health Medicine Life Sciences, Maastricht University Medical Center+, Maastricht University, 6229 ER Maastricht, the Netherlands
  • 56 Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6500 AH Nijmegen, the Netherlands; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands
  • 57 Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27713, USA
  • 58 Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center+, azM, 6202 AZ Maastricht, the Netherlands
  • 59 University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA; Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA
  • 60 Department of Neurology and Laboratory of Neuroimmunology, The Agnes Ginges Center for Neurogenetics, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, 91120 Jerusalem, Israel
  • 61 Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil
  • 62 Division of Medical Genetics & Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA
  • 63 Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany
  • 64 Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada
  • 65 The University of Kansas School of Medicine Salina Campus, Salina, KS 67401, USA
  • 66 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
  • 67 Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6500 AH Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands. Electronic address: simon.fisher@mpi.nl
Am J Hum Genet, 2021 02 04;108(2):346-356.
PMID: 33513338 DOI: 10.1016/j.ajhg.2021.01.007

Abstract

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.