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
  • 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: [email protected].
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.