2. Academic Validation
  3. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

  • Am J Hum Genet. 2021 Feb 4;108(2):346-356. doi: 10.1016/j.ajhg.2021.01.007.
Joery den Hoed 1,  Elke de Boer 2,  Norine Voisin 3,  Alexander J M Dingemans 2,  Nicolas Guex 4,  Laurens Wiel 5,  Christoffer Nellaker 6,  Shivarajan M Amudhavalli 7,  Siddharth Banka 8,  Frederique S Bena 9,  Bruria Ben-Zeev 10,  Vincent R Bonagura 11,  Ange-Line Bruel 12,  Theresa Brunet 13,  Han G Brunner 14,  Hui B Chew 15,  Jacqueline Chrast 3,  Loreta Cimbalistienė 16,  Hilary Coon 17,  DDD Study 18,  Emmanuèlle C Délot 19,  Florence Démurger 20,  Anne-Sophie Denommé-Pichon 12,  Christel Depienne 21,  Dian Donnai 8,  David A Dyment 22,  Orly Elpeleg 23,  Laurence Faivre 24,  Christian Gilissen 25,  Leslie Granger 26,  Benjamin Haber 27,  Yasuo Hachiya 28,  Yasmin Hamzavi Abedi 29,  Jennifer Hanebeck 27,  Jayne Y Hehir-Kwa 30,  Brooke Horist 31,  Toshiyuki Itai 32,  Adam Jackson 33,  Rosalyn Jewell 34,  Kelly L Jones 35,  Shelagh Joss 36,  Hirofumi Kashii 28,  Mitsuhiro Kato 37,  Anja A Kattentidt-Mouravieva 38,  Fernando Kok 39,  Urania Kotzaeridou 27,  Vidya Krishnamurthy 31,  Vaidutis Kučinskas 16,  Alma Kuechler 21,  Alinoë Lavillaureix 40,  Pengfei Liu 41,  Linda Manwaring 42,  Naomichi Matsumoto 32,  Benoît Mazel 43,  Kirsty McWalter 44,  Vardiella Meiner 23,  Mohamad A Mikati 45,  Satoko Miyatake 32,  Takeshi Mizuguchi 32,  Lip H Moey 46,  Shehla Mohammed 47,  Hagar Mor-Shaked 23,  Hayley Mountford 48,  Ruth Newbury-Ecob 49,  Sylvie Odent 40,  Laura Orec 27,  Matthew Osmond 22,  Timothy B Palculict 44,  Michael Parker 50,  Andrea K Petersen 26,  Rolph Pfundt 51,  Eglė Preikšaitienė 16,  Kelly Radtke 52,  Emmanuelle Ranza 53,  Jill A Rosenfeld 54,  Teresa Santiago-Sim 44,  Caitlin Schwager 7,  Margje Sinnema 55,  Lot Snijders Blok 56,  Rebecca C Spillmann 57,  Alexander P A Stegmann 58,  Isabelle Thiffault 59,  Linh Tran 45,  Adi Vaknin-Dembinsky 60,  Juliana H Vedovato-Dos-Santos 61,  Samantha A Schrier Vergano 62,  Eric Vilain 19,  Antonio Vitobello 12,  Matias Wagner 63,  Androu Waheeb 64,  Marcia Willing 42,  Britton Zuccarelli 65,  Usha Kini 66,  Dianne F Newbury 48,  Tjitske Kleefstra 2,  Alexandre Reymond 3,  Simon E Fisher 67,  Lisenka E L M Vissers 2
Affiliations

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.
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.

Keywords

HPO-based analysis; SATB1; cell-based functional assays; de novo variants; intellectual disability; neurodevelopmental disorders; seizures; teeth abnormalities.

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