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.

MBD5 haploinsufficiency is associated with sleep disturbance and disrupts circadian pathways common to Smith–Magenis and fragile X syndromes

“…We tested the expression of MBD5 to confirm MBD5 haploinsufficiency in the del 2q23.1 cell lines, which was consistent with previous studies (Figure 1). 26 Based on literature indicating altered expression of circadian genes in SMS LCLs, we tested the expression of four circadian genes, NR1D2, PER1, PER2, and PER3, in 2q23.1 deletion syndrome LCLs that were grown at the same time and under the same conditions. 23 The transcript levels of the above four circadian rhythm genes had significantly reduced mRNA expression in del 2q23.1 LCLs (Figure 1).…”

“…Thus, through microarray technology, we investigated the effect of knocking down MBD5 for 24 and 32 h with siRNA to levels that mimic expression seen in del 2q23.1 patients (~50-60% of normal expression) on circadian gene expression in SH-SY5Y cell lines. 4,26 We first knocked down MBD5 in HEK293T cells to test the efficacy in knocking down MBD5 and then proceeded to SH-SY5Y lines, which are less robust and harder to transfect. Real-time qRT-PCR showed 60% knockdown of MBD5 was achieved in HEK293T and SH-SY5Y cells (Supplementary Figure S1).…”

“…These sleep studies further support previous reports regarding del 2q23.1 patients' sleep habits. [4][5][6][7][8][9][10][11][12] Although this survey may reflect a subjective measure of the sleep phenotype present in 2q23.1 deletion syndrome patients as parents/guardians answered the survey, parents are in a unique position to describe their child's regular sleep behaviors. Importantly,~55.6% of parents reported that they use medication to improve the poor sleep patterns in their children, which is a significant indicator of the difficulties faced by the child and the family because of the sleep problems.…”

“…4 Sleep disturbance have been previously reported in a few cases. [4][5][6][7][8][9][10][11][12] Some of the sleep disturbances mentioned in these cases are waking 6-8 times per night, apparent night terrors in the early part of sleep, and waking in the early hours of the morning. [4][5][6][7][8][9][10][11][12] Although it is clear a sleep disturbance exists in del 2q23.1, no systematic characterization of the extent of sleep problems in this population has been published.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Interestingly, both NRXN1 and the postsynaptic binding partners NLGN1-4 have been strongly implicated in autism and reviewed elsewhere [106,[167][168][169][170]. MBD5, a methylCpG-binding domain gene, has been identified as the causal gene in the 2q23.1 locus, which is characterized by ASD and ID [171,172]. Deletions encompassing the C-terminus of AUTS2 are associated with autistic features and developmental delay [173].…”