RGD Reference Report - Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder. - Rat Genome Database

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Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.

Authors: Mullegama, SV  Rosenfeld, JA  Orellana, C  Van Bon, BW  Halbach, S  Repnikova, EA  Brick, L  Li, C  Dupuis, L  Rosello, M  Aradhya, S  Stavropoulos, DJ  Manickam, K  Mitchell, E  Hodge, JC  Talkowski, ME  Gusella, JF  Keller, K  Zonana, J  Schwartz, S  Pyatt, RE  Waggoner, DJ  Shaffer, LG  Lin, AE  De Vries, BB  Mendoza-Londono, R  Elsea, SH 
Citation: Mullegama SV, etal., Eur J Hum Genet. 2014 Jan;22(1):57-63. doi: 10.1038/ejhg.2013.67. Epub 2013 May 1.
RGD ID: 11554207
Pubmed: PMID:23632792   (View Abstract at PubMed)
PMCID: PMC3865402   (View Article at PubMed Central)
DOI: DOI:10.1038/ejhg.2013.67   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
autism spectrum disorder  IAGP 11554207DNA:duplication and deletion: :RGD 
autism spectrum disorder  ISOMBD5 (Homo sapiens)11554207; 11554207DNA:duplication and deletion: :RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mbd5  (methyl-CpG binding domain protein 5)

Genes (Mus musculus)
Mbd5  (methyl-CpG binding domain protein 5)

Genes (Homo sapiens)
MBD5  (methyl-CpG binding domain protein 5)


Additional Information