Refinement of the critical 2p25.3 deletion region: the role of MYT1L in intellectual disability and obesity

Genet Med. 2015 Jun;17(6):460-6. doi: 10.1038/gim.2014.124.

Nina De Rocker ¹, Sarah Vergult ¹, David Koolen ², Eva Jacobs ¹, Alexander Hoischen ², Susan Zeesman ³, Birgitte Bang ⁴, Frédérique Béna ⁵, Nele Bockaert ⁶, Ernie M Bongers ², Thomy de Ravel ⁷, Koenraad Devriendt ⁷, Sabrina Giglio ⁸, Laurence Faivre ⁹, Shelagh Joss ¹⁰, Saskia Maas ¹¹, Nathalie Marle ⁹, Francesca Novara ¹², Malgorzata J M Nowaczyk ¹³, Hilde Peeters ⁷, Abeltje Polstra ¹¹, Filip Roelens ¹⁴, Carla Rosenberg ¹⁵, Julien Thevenon ⁹, Zeynep Tümer ¹⁶, Suzanne Vanhauwaert ¹, Konstantinos Varvagiannis ⁵, Andy Willaert ¹, Marjolein Willemsen ², Marjolaine Willems ¹⁷, Orsetta Zuffardi ¹², Paul Coucke ¹, Frank Speleman ¹, Evan E Eichler ¹⁸, Tjitske Kleefstra ², Björn Menten ¹

Affiliations

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.

PMID: 25232846 DOI: 10.1038/gim.2014.124

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.

Name
Email *

	Sorry, but the email address you supplied was invalid.