European Journal of Human Genetics - Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder
Article
European Journal of Human Genetics (2014) 22, 57–63; doi:10.1038/ejhg.2013.67; published online 1 May 2013
Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder
Sureni V Mullegama1, Jill A Rosenfeld2, Carmen Orellana3, Bregje W M van Bon4, Sara Halbach5, Elena A Repnikova6, Lauren Brick7, Chumei Li7, Lucie Dupuis8, Monica Rosello3, Swaroop Aradhya9, D James Stavropoulos10,11, Kandamurugu Manickam12, Elyse Mitchell13,14, Jennelle C Hodge13,14, Michael E Talkowski15,16,17, James F Gusella16,17,18, Kory Keller19, Jonathan Zonana19, Stuart Schwartz20, Robert E Pyatt6, Darrel J Waggoner5, Lisa G Shaffer21, Angela E Lin15,22, Bert B A de Vries4, Roberto Mendoza-Londono8 and Sarah H Elsea1,23,24
- 1Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
- 2Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA, USA
- 3Service of Genetics and Prenatal Diagnosis, University and Polytechnic Hospital La Fe, Valencia, Spain
- 4Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
- 5Department of Human Genetics, University of Chicago, Chicago, IL, USA
- 6Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
- 7Department of Pediatrics, Clinical Genetics Program, McMaster University Medical Center and McMaster Children’s Hospital, Hamilton, Ontario, Canada
- 8Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
- 9GeneDx, Gaithersburg, MD, USA
- 10Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
- 11Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada
- 12Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA
- 13Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
- 14Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
- 15Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
- 16Program in Medical and Population Genetics, Broad Institute of Harvard and M.I.T., Cambridge, MA, USA
- 17Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA
- 18Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
- 19Department of Molecular and Medical Genetics, Child Development and Rehabilitation Center, Oregon Health and Science University, Portland, OR, USA
- 20Laboratory Corporation of America, Research Triangle Park, Durham, NC, USA
- 21Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA, USA
- 22Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, USA
- 23Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
- 24Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Correspondence: Dr SH Elsea, FACMG, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 USA. Tel: +1 713 798 5484; Fax: +1 713 798 2787; E-mail: elsea@bcm.edu
Received 30 November 2012; Revised 26 January 2013; Accepted 14 February 2013
Advance online publication 1 May 2013
Advance online publication 1 May 2013
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Abstract
Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication ofMBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.
Keywords:
MBD5; gene dosage; 2q23.1; autism spectrum disorder; microduplication; microdeletion
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