ArticleAmerican journal of human genetics2021
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 54 citations in OpenAlex.
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Authors and funding
98 authors at 20 institutions in 12 countries.
Joery den HoedLanguage 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.
Elke de BoerDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands.
Norine VoisinCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Alexander J M DingemansDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands.
Nicolas GuexCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Bioinformatics Competence Center, University of Lausanne, 1015 Lausanne, Switzerland.
Laurens WielDepartment 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.
Christoffer NellakerNuffield 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.
Shivarajan M AmudhavalliUniversity 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.
Siddharth BankaManchester 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.
Frederique S BenaService of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland.
Bruria Ben-ZeevEdmomd and Lilly Safra Pediatric Hospital, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
Vincent R BonaguraInstitute 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.
Ange-Line BruelUMR1231-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.
Theresa BrunetInstitute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
Han G BrunnerDepartment 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.
Hui B ChewDepartment of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia.
Jacqueline ChrastCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Loreta CimbalistienėDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania.
Hilary CoonDepartment of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
DDD StudyWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Emmanuèlle C DélotCenter 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.
Florence DémurgerDepartment of clinical genetics, Vannes hospital, 56017 Vannes, France.
Anne-Sophie Denommé-PichonUMR1231-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.
Christel DepienneInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Dian DonnaiManchester 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.
David A DymentChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada.
Orly ElpelegDepartment of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel.
Laurence FaivreUMR1231-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.
Christian GilissenDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Leslie GrangerDepartment of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.
Benjamin HaberDivision of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Yasuo HachiyaDepartment of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo 183-0042, Japan.
Yasmin Hamzavi AbediDivision 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.
Jennifer HanebeckDivision of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Jayne Y Hehir-KwaPrincess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands.
Brooke HoristPediatrics & Genetics, Alpharetta, GA 30005, USA.
Toshiyuki ItaiDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
Adam JacksonManchester 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.
Rosalyn JewellYorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK.
Kelly L JonesDivision 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.
Shelagh JossWest of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
Hirofumi KashiiDepartment of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo 183-0042, Japan.
Mitsuhiro KatoDepartment of Pediatrics, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8666, Japan.
Anja A Kattentidt-MouravievaZuidwester, 3240AA Middelharnis, the Netherlands.
Fernando KokMendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil; University of Sao Paulo, School of Medicine, Sao Paulo, SP 01246-903, Brazil.
Urania KotzaeridouDivision of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Vidya KrishnamurthyPediatrics & Genetics, Alpharetta, GA 30005, USA.
Vaidutis KučinskasDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.
Alinoë LavillaureixCHU Rennes, Univ Rennes, CNRS, IGDR, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 35033 Rennes, France.
Pengfei LiuDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
Linda ManwaringDepartment of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Naomichi MatsumotoDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
Benoît MazelCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
Kirsty McWalterGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Vardiella MeinerDepartment of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel.
Mohamad A MikatiDivision of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, USA.
Satoko MiyatakeDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
Takeshi MizuguchiDepartment of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
Lip H MoeyDepartment of Genetics, Penang General Hospital, Jalan Residensi, 10990 Georgetown, Penang, Malaysia.
Shehla MohammedClinical Genetics, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
Hagar Mor-ShakedDepartment of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel.
Hayley MountfordDepartment of Biological and Medical Sciences, Headington Campus, Oxford Brookes University, Oxford OX3 0BP, UK.
Ruth Newbury-EcobClinical Genetics, St Michael's Hospital Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8EG, UK.
Sylvie OdentCHU Rennes, Univ Rennes, CNRS, IGDR, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 35033 Rennes, France.
Laura OrecDivision of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
Matthew OsmondChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada.
Timothy B PalculictGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Michael ParkerSheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S5 7AU, UK.
Andrea K PetersenDepartment of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.
Rolph PfundtDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands.
Eglė PreikšaitienėDepartment of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania.
Kelly RadtkeClinical Genomics Department, Ambry Genetics, Aliso Viejo, CA 92656, USA.
Emmanuelle RanzaService of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Teresa Santiago-SimGeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
Caitlin SchwagerUniversity 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.
Margje SinnemaDepartment 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.
Lot Snijders BlokLanguage 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.
Rebecca C SpillmannDepartment of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27713, USA.
Alexander P A StegmannDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center+, azM, 6202 AZ Maastricht, the Netherlands.
Isabelle ThiffaultUniversity 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.
Linh TranDivision of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, USA.
Adi Vaknin-DembinskyDepartment 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.
Juliana H Vedovato-Dos-SantosMendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil.
Samantha A Schrier VerganoDivision of Medical Genetics & Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA.
Eric VilainCenter 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.
Antonio VitobelloUMR1231-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.
Matias WagnerInstitute of Human Genetics, Technical University of Munich, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany.
Androu WaheebChildren'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.
Marcia WillingDepartment of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA.
Britton ZuccarelliThe University of Kansas School of Medicine Salina Campus, Salina, KS 67401, USA.
Usha KiniOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
Dianne F NewburyDepartment of Biological and Medical Sciences, Headington Campus, Oxford Brookes University, Oxford OX3 0BP, UK.
Tjitske KleefstraDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands.
Alexandre ReymondCenter for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Simon E FisherLanguage 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.
Lisenka E L M VissersDepartment of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands.
Radboud University Nijmegen · NLHeidelberg University · DEInserm · FRUniversity of Lausanne · CHYokohama City University · JPChildren's Hospital of Eastern Ontario · CAChildren's Mercy Hospital · USDuke Medical Center · USHadassah Medical Center · ILUniversity of Manchester · GBVilnius University · LTBaylor College of Medicine · USCentre National de la Recherche Scientifique · FRChildren's National · USLegacy Emanuel Medical Center · USOxford Brookes University · GBPediatrics and Genetics · USTokyo Metropolitan Neurological Hospital · JPUniversity of Duisburg-Essen · DEWashington University in St. Louis · US
Funding
Medical Research Council MR/M014568/1
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.
Indexed as
MutationChromatinFemaleGenetic Association StudiesHaploinsufficiencyHumansMaleMatrix Attachment Region Binding ProteinsModels, MolecularMutation, MissenseNeurodevelopmental DisordersProtein BindingProtein DomainsTranscription, GeneticChromatinMatrix Attachment Region Binding ProteinsSATB1 protein, humancell-based functional assaysde novo variantsHPO-based analysisintellectual disabilityneurodevelopmental disordersSATB1seizuresteeth abnormalities
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