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

Autor:	den Hoed J; 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., de Boer E; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands., Voisin N; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland., Dingemans AJM; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands., Guex N; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Bioinformatics Competence Center, University of Lausanne, 1015 Lausanne, Switzerland., Wiel L; 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., Nellaker C; 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., Amudhavalli SM; 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., Banka S; 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., Bena FS; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland., Ben-Zeev B; Edmomd and Lilly Safra Pediatric Hospital, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel., Bonagura VR; 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., Bruel AL; 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., Brunet T; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany., Brunner HG; 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., Chew HB; Department of Genetics, Kuala Lumpur Hospital, Jalan Pahang, 50586 Kuala Lumpur, Malaysia., Chrast J; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland., Cimbalistienė L; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania., Coon H; Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA., Délot EC; 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., Démurger F; Department of clinical genetics, Vannes hospital, 56017 Vannes, France., Denommé-Pichon AS; 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., Depienne C; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany., Donnai D; 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., Dyment DA; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada., Elpeleg O; Department of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel., Faivre L; 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., Gilissen C; 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., Granger L; Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA., Haber B; Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Hachiya Y; Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo 183-0042, Japan., Abedi YH; 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., Hanebeck J; Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Hehir-Kwa JY; Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands., Horist B; Pediatrics & Genetics, Alpharetta, GA 30005, USA., Itai T; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan., Jackson A; 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., Jewell R; Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds LS7 4SA, UK., Jones KL; 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., Joss S; West of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK., Kashii H; Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Fuchu, Tokyo 183-0042, Japan., Kato M; Department of Pediatrics, Showa University School of Medicine, Shinagawa-ku, Tokyo 142-8666, Japan., Kattentidt-Mouravieva AA; Zuidwester, 3240AA Middelharnis, the Netherlands., Kok F; Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil; University of Sao Paulo, School of Medicine, Sao Paulo, SP 01246-903, Brazil., Kotzaeridou U; Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Krishnamurthy V; Pediatrics & Genetics, Alpharetta, GA 30005, USA., Kučinskas V; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania., Kuechler A; Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany., Lavillaureix A; CHU Rennes, Univ Rennes, CNRS, IGDR, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 35033 Rennes, France., Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA., Manwaring L; Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA., Matsumoto N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan., Mazel B; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France., McWalter K; GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Meiner V; Department of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel., Mikati MA; Division of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, USA., Miyatake S; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan., Mizuguchi T; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan., Moey LH; Department of Genetics, Penang General Hospital, Jalan Residensi, 10990 Georgetown, Penang, Malaysia., Mohammed S; Clinical Genetics, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Mor-Shaked H; Department of Genetics, Hadassah Medical Center, Hebrew University Medical Center, 91120 Jerusalem, Israel., Mountford H; Department of Biological and Medical Sciences, Headington Campus, Oxford Brookes University, Oxford OX3 0BP, UK., Newbury-Ecob R; Clinical Genetics, St Michael's Hospital Bristol, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8EG, UK., Odent S; CHU Rennes, Univ Rennes, CNRS, IGDR, Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, Hôpital Sud, 35033 Rennes, France., Orec L; Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Osmond M; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada., Palculict TB; GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Parker M; Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S5 7AU, UK., Petersen AK; Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA., Pfundt R; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands., Preikšaitienė E; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 08661 Vilnius, Lithuania., Radtke K; Clinical Genomics Department, Ambry Genetics, Aliso Viejo, CA 92656, USA., Ranza E; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Santiago-Sim T; GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA., Schwager C; 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., Sinnema M; 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., Snijders Blok L; 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., Spillmann RC; Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27713, USA., Stegmann APA; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center+, azM, 6202 AZ Maastricht, the Netherlands., Thiffault I; 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., Tran L; Division of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, USA., Vaknin-Dembinsky A; 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., Vedovato-Dos-Santos JH; Mendelics Genomic Analysis, Sao Paulo, SP 04013-000, Brazil., Schrier Vergano SA; Division of Medical Genetics & Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA., Vilain E; 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., Vitobello A; 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., Wagner M; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, 85764 Munich, Germany., Waheeb A; 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., Willing M; Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110-1093, USA., Zuccarelli B; The University of Kansas School of Medicine Salina Campus, Salina, KS 67401, USA., Kini U; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK., Newbury DF; Department of Biological and Medical Sciences, Headington Campus, Oxford Brookes University, Oxford OX3 0BP, UK., Kleefstra T; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands., Reymond A; Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland., Fisher SE; 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., Vissers LELM; Department of Human Genetics, Radboudumc, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500 GL Nijmegen, the Netherlands.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2021 Feb 04; Vol. 108 (2), pp. 346-356. Date of Electronic Publication: 2021 Jan 28.
DOI:	10.1016/j.ajhg.2021.01.007
Abstrakt:	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. (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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