Ivan Ivanovski1,2, Olivera Djuric1,3, Stefano Giuseppe Caraffi1, Daniela Santodirocco1, Marzia Pollazzon1, Simonetta Rosato1, Duccio Maria Cordelli4, Ebtesam Abdalla5, Patrizia Accorsi6, Margaret P Adam7, Paola Francesca Ajmone8, Magdalena Badura-Stronka9, Chiara Baldo10, Maddalena Baldi1, Allan Bayat11,12, Stefania Bigoni13, Federico Bonvicini1,14, Jeroen Breckpot15, Bert Callewaert16, Guido Cocchi17, Goran Cuturilo18,19, Daniele De Brasi20, Koenraad Devriendt15, Mary Beth Dinulos21, Tina Duelund Hjortshøj22, Roberta Epifanio23, Francesca Faravelli24, Agata Fiumara25, Debora Formisano26, Lucio Giordano6, Marina Grasso10, Sabine Grønborg27, Alessandro Iodice28, Lorenzo Iughetti14, Vladimir Kuburovic29, Anna Kutkowska-Kazmierczak30, Didier Lacombe31,32, Caterina Lo Rizzo33, Anna Luchetti34, Baris Malbora35, Isabella Mammi36, Francesca Mari33, Giulia Montorsi1,37, Sebastien Moutton31,32, Rikke S Møller38,39, Petra Muschke40, Jens Erik Klint Nielsen41, Ewa Obersztyn30, Chiara Pantaleoni42, Alessandro Pellicciari4, Maria Antonietta Pisanti43, Igor Prpic44, Maria Luisa Poch-Olive45, Federico Raviglione46, Alessandra Renieri33, Emilia Ricci4, Francesca Rivieri47, Gijs W Santen48, Salvatore Savasta49, Gioacchino Scarano50, Ina Schanze40, Angelo Selicorni51,52, Margherita Silengo53, Robert Smigiel54, Luigina Spaccini55, Giovanni Sorge56, Krzysztof Szczaluba57, Luigi Tarani58, Luis Gonzaga Tone59, Annick Toutain60, Aurelien Trimouille31,32, Elvis Terci Valera59, Samantha Schrier Vergano61,62, Nicoletta Zanotta24, Martin Zenker40, Andrea Conidi63, Marcella Zollino64, Anita Rauch65, Christiane Zweier66, Livia Garavelli67. 1. Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy. 2. Department of Surgical, Medical, Dental, and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy. 3. Institute of Epidemiology, School of Medicine, University of Belgrade, Belgrade, Serbia. 4. Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy. 5. Department of Human Genetics, Medical Research Institute, University of Alexandria, Alexandria, Egypt. 6. Neuropsychiatric Department, Spedali Civili Brescia, Brescia, Italy. 7. Division of Genetic Medicine, University of Washington School of Medicine, Seattle, Washington, USA. 8. Child and Adolescent Neuropsychiatric Service (UONPIA) Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 9. Chair and Department of Medical Genetics, Poznan University of Medical Sciences, Poznań, Poland. 10. Laboratory of Human Genetics; Galliera Hospital, Genoa, Italy. 11. Department of Pediatrics, University Hospital of Copenhagen/Hvidovre, Copenhagen, Denmark. 12. Department of Clinical Genetics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. 13. UOL of Medical Genetics, University Hospital of Ferrara, Ferrara, Italy. 14. Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy. 15. Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium. 16. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 17. Neonatology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. 18. Faculty of Medicine, University of Belgrade, Belgrade, Serbia. 19. Department of Medical Genetics, University Children's Hospital, Belgrade, Serbia. 20. Department of Pediatrics, AORN Santobono Pausilipon, Naples, Italy. 21. Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA. 22. Department of Clinical Genetics, Kennedy Center, Glostrup, Denmark. 23. Clinical Neurophysiology Unit, IRCCS, E Medea Scientific Institute, Bosisio Parini, Lecco, Italy. 24. Clinical Genetics, NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. 25. Department of Clinical and Experimental Medicine, Regional Referral Center for Inborn Errors Metabolism, Pediatric Clinic, University of Catania, Catania, Italy. 26. Scientific Directorate, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy. 27. Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark. 28. Neuropsychiatric Department, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy. 29. Department of Cardiology, Mother and Child Health Care Institute, Belgrade, Serbia. 30. Department of Medical Genetics, Institute of the Mother and Child, Warsaw, Poland. 31. CHU de Bordeaux, Service de Génétique Médicale, Bordeaux, France. 32. INSERM U1211, Univ. Bordeaux, Bordeaux, France. 33. Medical Genetics, University of Siena, Siena, Italy. 34. Child Neuropsychiatry Unit, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy. 35. Department of Pediatric Hematology & Oncology, Tepecik Training and Research Hospital, Izmir, Turkey. 36. Medical Genetics Unit, Dolo Hospital, Venice, Italy. 37. Faculty of Medicine, University of Modena and Reggio Emilia, Modena, Italy. 38. Danish Epilepsy Centre, Dianalund, Denmark. 39. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 40. Institute for Human Genetics, University Hospital Magdeburg, Magdeburg, Germany. 41. Department of Pediatrics, Zealand University Hospital Roskilde, Roskilde, Denmark. 42. Developmental Neurology Department, IRCCS Fondazione Istituto Neurologico "C. Besta,", Milan, Italy. 43. Medical Genetic Unit, AORN Cardarelli, Naples, Italy. 44. Department of Pediatrics-Child Neurology Service, University Hospital Rijeka, Medical Faculty, University of Rijeka, Rijeka, Croatia. 45. Department of Pediatrics, H. San Pedro, La Rioja, Logrono, Spain. 46. Child Neuropsychiatry Unit, U.O.N.P.I.A ASST-Rhodense, Rho, Milan, Italy. 47. Genetics Unit, St. Chiara Hospital, Trento, Italy. 48. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 49. Department of Pediatrics, IRCCS San Matteo, Pavia, Italy. 50. Department of Medical Genetics, Gaetano Rummo Hospital, Benevento, Italy. 51. Department of Pediatrics, Hospital S. Gerardo, University of Milano-Bicocca, Monza, Italy. 52. Department of Pediatrics, ASST Lariana, Como, Italy. 53. Department of Pediatrics, University of Torino, Torino, Italy. 54. Department of Genetics, Wroclaw Medical University, Wroclaw, Poland. 55. Clinical Genetics Unit, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, V. Buzzi Children's Hospital, Universita' degli Studi di Milano, Milan, Italy. 56. Department of Pediatrics and Medical Sciences, "Vittorio Emanuele" Hospital, University of Catania, Catania, Italy. 57. Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland. 58. Department of Pediatrics, University "La Sapienza,", Rome, Italy. 59. Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. 60. Department of Genetics, Tours University Hospital, Tours, France. 61. Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia, USA. 62. Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia, USA. 63. Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands. 64. Institute of Genomic Medicine, Catholic University, Gemelli Hospital Foundation, Rome, Italy. 65. Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland. 66. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. 67. Clinical Genetics Unit, Department of Obstetrics and Pediatrics, AUSL-IRCCS of Reggio Emilia, Reggio Emilia, Italy. livia.garavelli@ausl.re.it.
Abstract
PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
PURPOSE: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS. METHODS: In a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations. RESULTS: All anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations. CONCLUSION: Knowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.
Authors: Judith C Birkhoff; Rutger W W Brouwer; Petros Kolovos; Anne L Korporaal; Ana Bermejo-Santos; Ilias Boltsis; Karol Nowosad; Mirjam C G N van den Hout; Frank G Grosveld; Wilfred F J van IJcken; Danny Huylebroeck; Andrea Conidi Journal: Hum Mol Genet Date: 2020-08-29 Impact factor: 6.150
Authors: Elena Díaz-Casado; Ricardo Gómez-Nieto; José M de Pereda; Luis J Muñoz; María Jara-Acevedo; Dolores E López Journal: PLoS One Date: 2020-03-13 Impact factor: 3.240
Authors: Katie Frith; C Mee Ling Munier; Lucy Hastings; David Mowat; Meredith Wilson; Nabila Seddiki; Rebecca Macintosh; Anthony D Kelleher; Paul Gray; John James Zaunders Journal: Int J Mol Sci Date: 2021-05-18 Impact factor: 5.923