Nina De Rocker1, Sarah Vergult1, David Koolen2, Eva Jacobs1, Alexander Hoischen2, Susan Zeesman3, Birgitte Bang4, Frédérique Béna5, Nele Bockaert6, Ernie M Bongers2, Thomy de Ravel7, Koenraad Devriendt7, Sabrina Giglio8, Laurence Faivre9, Shelagh Joss10, Saskia Maas11, Nathalie Marle9, Francesca Novara12, Malgorzata J M Nowaczyk13, Hilde Peeters7, Abeltje Polstra11, Filip Roelens14, Carla Rosenberg15, Julien Thevenon9, Zeynep Tümer16, Suzanne Vanhauwaert1, Konstantinos Varvagiannis5, Andy Willaert1, Marjolein Willemsen2, Marjolaine Willems17, Orsetta Zuffardi12, Paul Coucke1, Frank Speleman1, Evan E Eichler18, Tjitske Kleefstra2, Björn Menten1. 1. Center for Medical Genetics, Ghent University, Ghent, Belgium. 2. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. 3. Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada. 4. Paediatric Department, Copenhagen University Hospital, Herlev, Denmark. 5. Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. 6. Center for Developmental Disorders, Ghent University Hospital, Ghent, Belgium. 7. Center for Human Genetics, Leuven University Hospitals, KU Leuven, Leuven, Belgium. 8. Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy. 9. Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU de Dijon, Dijon, France. 10. West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Southern General Hospital, Glasgow, UK. 11. Department of Clinical Genetics, Academic Medical Center, UVA, Amsterdam, The Netherlands. 12. Department of Molecular Medicine, University of Pavia, Pavia, Italy. 13. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. 14. Heilig Hart Ziekenhuis Roeselare-Menen, Roeselare, Belgium. 15. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil. 16. Center for Applied Human Molecular Genetics, Kennedy Center, University of Copenhagen, Glostrup, Denmark. 17. Département de Génétique Clinique, CHRU de Montpellier, Hôpital Arnaud de Villeneuve, Montpellier, France. 18. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
Abstract
PURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.
PURPOSE: Submicroscopic deletions of chromosome band 2p25.3 are associated with intellectual disability and/or central obesity. Although MYT1L is believed to be a critical gene responsible for intellectual disability, so far no unequivocal data have confirmed this hypothesis. METHODS: In this study we evaluated a cohort of 22 patients (15 sporadic patients and two families) with a 2p25.3 aberration to further refine the clinical phenotype and to delineate the role of MYT1L in intellectual disability and obesity. In addition, myt1l spatiotemporal expression in zebrafish embryos was analyzed by quantitative polymerase chain reaction and whole-mount in situ hybridization. RESULTS: Complete MYT1L deletion, intragenic deletion, or duplication was observed in all sporadic patients, in addition to two patients with a de novo point mutation in MYT1L. The familial cases comprise a 6-Mb deletion in a father and his three children and a 5' MYT1L overlapping duplication in a father and his two children. Expression analysis in zebrafish embryos shows specific myt1l expression in the developing brain. CONCLUSION: Our data strongly strengthen the hypothesis that MYT1L is the causal gene for the observed syndromal intellectual disability. Moreover, because 17 patients present with obesity/overweight, haploinsufficiency of MYT1L might predispose to weight problems with childhood onset.Genet Med 17 6, 460-466.
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