European Journal of Human Genetics - Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

full-text ►

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 Stavropoulos^10,11, Kandamurugu Manickam¹², Elyse Mitchell^13,14, Jennelle C Hodge^13,14, Michael E Talkowski^15,16,17, James F Gusella^16,17,18, Kory Keller¹⁹, Jonathan Zonana¹⁹, Stuart Schwartz²⁰, Robert E Pyatt⁶, Darrel J Waggoner⁵, Lisa G Shaffer²¹, Angela E Lin^15,22, Bert B A de Vries⁴, Roberto Mendoza-Londono⁸ and Sarah H Elsea^1,23,24

1. ¹Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
2. ²Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA, USA
3. ³Service of Genetics and Prenatal Diagnosis, University and Polytechnic Hospital La Fe, Valencia, Spain
4. ⁴Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
5. ⁵Department of Human Genetics, University of Chicago, Chicago, IL, USA
6. ⁶Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
7. ⁷Department of Pediatrics, Clinical Genetics Program, McMaster University Medical Center and McMaster Children’s Hospital, Hamilton, Ontario, Canada
8. ⁸Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
9. ⁹GeneDx, Gaithersburg, MD, USA
10. ¹⁰Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
11. ¹¹Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada
12. ¹²Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA
13. ¹³Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
14. ¹⁴Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA
15. ¹⁵Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
16. ¹⁶Program in Medical and Population Genetics, Broad Institute of Harvard and M.I.T., Cambridge, MA, USA
17. ¹⁷Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA
18. ¹⁸Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
19. ¹⁹Department of Molecular and Medical Genetics, Child Development and Rehabilitation Center, Oregon Health and Science University, Portland, OR, USA
20. ²⁰Laboratory Corporation of America, Research Triangle Park, Durham, NC, USA
21. ²¹Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA, USA
22. ²²Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, USA
23. ²³Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
24. 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

Topof page

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