Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder - PubMed (original) (raw)

doi: 10.1038/ejhg.2013.67. Epub 2013 May 1.

Jill A Rosenfeld 2, Carmen Orellana 3, Bregje W M van Bon 4, Sara Halbach 5, Elena A Repnikova 6, Lauren Brick 7, Chumei Li 7, Lucie Dupuis 8, Monica Rosello 3, Swaroop Aradhya 9, D James Stavropoulos 10, Kandamurugu Manickam 11, Elyse Mitchell 12, Jennelle C Hodge 12, Michael E Talkowski 13, James F Gusella 14, Kory Keller 15, Jonathan Zonana 15, Stuart Schwartz 16, Robert E Pyatt 6, Darrel J Waggoner 5, Lisa G Shaffer 17, Angela E Lin 18, Bert B A de Vries 4, Roberto Mendoza-Londono 8, Sarah H Elsea 19

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

Sureni V Mullegama et al. Eur J Hum Genet. 2014 Jan.

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.

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Figures

Figure 1

Figure 1

Delineation of the 2q23.1 critical region. Schematic representation of _MBD5_-containing duplications in this report and key variants previously reported in the literature. Duplications are in blue and green, while deletions are in pink. Three previously reported duplications that were cytogenetically defined; thus, no coordinates were given. Boxes represent the minimum size of the deletions/duplications and the horizontal lines extend through gaps in coverage to show the maximum deletion/duplication sizes. Green boxes represent individuals with MBD5 expression studies reported here. Genes within the region are represented by orange boxes, and the shaded region shows the location of MBD5. All individuals are unrelated, and all cases are de novo with the exception of GC19184 (cases a and b) and GC3057 (cases a and b), 3424_3 (cases a and b) which represent parent/child pairs.

Figure 2

Figure 2

Features present in individuals with 2q23.1 duplication syndrome. Four individuals with 2q23.1 duplication are shown, (a) SMS409, 7 years; (b) SMS397, 7 years; (c) SMS376, 15 years; (d) Chung 2 2012, 17 years and (e) SMS381, 6 years. While some dysmorphic craniofacial features are present (high arched eyebrows, thin upper lip, periorbital fullness, downslanting palpebral fissures, triangular face), no significant consistent craniofacial findings among individuals with 2q23.1 duplication are appreciated.

Figure 3

Figure 3

Hand and foot anomalies present in individuals with 2q23.1 microduplication syndrome. (a) Hands of SMS376. Note the fifth finger clinodactyly. (b) Foot of SMS409. Note the large, broad first toe.

Figure 4

Figure 4

MBD5 expression is altered by deletion, duplication or disruption of the MBD5 gene. Quantitative real-time PCR expression analysis of MBD5 is shown in LCLs or peripheral blood lymphocytes from individuals with 2q23.1 deletions, 2q23.1 duplications, and normal controls using predesigned assays from Taqman MGB probes for MBD5 and GAPDH. GAPDH served as the endogenous control. Differences in transcript levels were quantified according to the ΔΔ_C_t method and normalized to GAPDH. Expression of all controls was normalized to 1.0. Acquired data were analyzed with 7500 Fast System SDS Software. Each bar represents mean (±SEM) of values from 3–10 independent experiments. Data show an expected range of expression for normal controls, 0.94- to 1.23-fold MBD5 expression in lymphocytes (BC1-2) and LCLs (LC1-7). Samples from 2q23.1 deletion syndrome patients show 0.22- to 0.59-fold expression of MBD5 (P<0.0001 for all cases). Samples from individuals with 2q23.1 duplication show overexpression of MBD5, ranging from 1.52- to 1.83-fold compared with normal controls (P<0.0001 for all cases). The expression changes observed indicate MBD5 is a dosage-sensitive gene. aTalkowski et al, 2011;bChung et al, 2012.

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