title: Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.
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 of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors: Sureni V
authors: SV
authors: Mullegama
authors: Signature Genomic Laboratories, PerkinElmer Inc., Spokane, WA, USA.
authors: Jill A
authors: JA
authors: Rosenfeld
authors: Service of Genetics and Prenatal Diagnosis, University and Polytechnic Hospital La Fe, Valencia, Spain.
authors: Carmen
authors: C
authors: Orellana
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Bregje W M
authors: BW
authors: van Bon
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Sara
authors: S
authors: Halbach
authors: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
authors: Elena A
authors: EA
authors: Repnikova
authors: Department of Pediatrics, Clinical Genetics Program, McMaster University Medical Center and McMaster Children's Hospital, Hamilton, Ontario, Canada.
authors: Lauren
authors: L
authors: Brick
authors: Department of Pediatrics, Clinical Genetics Program, McMaster University Medical Center and McMaster Children's Hospital, Hamilton, Ontario, Canada.
authors: Chumei
authors: C
authors: Li
authors: Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors: Lucie
authors: L
authors: Dupuis
authors: Service of Genetics and Prenatal Diagnosis, University and Polytechnic Hospital La Fe, Valencia, Spain.
authors: Monica
authors: M
authors: Rosello
authors: GeneDx, Gaithersburg, MD, USA.
authors: Swaroop
authors: S
authors: Aradhya
authors: 1] Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada.
authors: D James
authors: DJ
authors: Stavropoulos
authors: Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.
authors: Kandamurugu
authors: K
authors: Manickam
authors: 1] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA [2] Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA.
authors: Elyse
authors: E
authors: Mitchell
authors: 1] Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA [2] Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA.
authors: Jennelle C
authors: JC
authors: Hodge
authors: 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA [2] Program in Medical and Population Genetics, Broad Institute of Harvard and M.I.T., Cambridge, MA, USA [3] Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA.
authors: Michael E
authors: ME
authors: Talkowski
authors: 1] Program in Medical and Population Genetics, Broad Institute of Harvard and M.I.T., Cambridge, MA, USA [2] Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA [3] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors: James F
authors: JF
authors: Gusella
authors: Department of Molecular and Medical Genetics, Child Development and Rehabilitation Center, Oregon Health and Science University, Portland, OR, USA.
authors: Kory
authors: K
authors: Keller
authors: Department of Molecular and Medical Genetics, Child Development and Rehabilitation Center, Oregon Health and Science University, Portland, OR, USA.
authors: Jonathan
authors: J
authors: Zonana
authors: Laboratory Corporation of America, Research Triangle Park, Durham, NC, USA.
authors: Stuart
authors: S
authors: Schwartz
authors: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
authors: Robert E
authors: RE
authors: Pyatt
authors: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors: Darrel J
authors: DJ
authors: Waggoner
authors: Paw Print Genetics, Genetic Veterinary Sciences, Inc., Spokane, WA, USA.
authors: Lisa G
authors: LG
authors: Shaffer
authors: 1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA [2] Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, USA.
authors: Angela E
authors: AE
authors: Lin
authors: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Bert B A
authors: BB
authors: de Vries
authors: Department of Pediatrics, Division of Clinical and Metabolic Genetics, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
authors: Roberto
authors: R
authors: Mendoza-Londono
authors: 1] Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA [2] Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA [3] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors: Sarah H
authors: SH
authors: Elsea
mesh_terms: D000293:Adolescent; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D002872:Chromosome Deletion; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics*; D002658:Developmental Disabilities / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007223:Infant; D008297:Male; D014314:Trisomy / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C550332:MBD5 protein, human
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