The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1

Abstract

The methyl-CpG-binding domain (MBD) gene family was first linked to autism over a decade ago when Rett syndrome, which falls under the umbrella of autism spectrum disorders (ASDs), was revealed to be predominantly caused by MECP2 mutations. Since that time, MECP2 alterations have been recognized in idiopathic ASD patients by us and others. Individuals with deletions across the MBD5 gene also present with ASDs, impaired speech, intellectual difficulties, repetitive behaviors, and epilepsy. These findings suggest that further investigations of the MBD gene family may reveal additional associations related to autism. We now describe the first study evaluating individuals with ASD for rare variants in four autosomal MBD family members, MBD5, MBD6, SETDB1, and SETDB2, and expand our initial screening in the MECP2 gene. Each gene was sequenced over all coding exons and evaluated for copy number variations in 287 patients with ASD and an equal number of ethnically matched control individuals. We identified 186 alterations through sequencing, approximately half of which were novel (96 variants, 51.6%). We identified seventeen ASD specific, nonsynonymous variants, four of which were concordant in multiplex families: MBD5 Tyr1269Cys, MBD6 Arg883Trp, MECP2 Thr240Ser, and SETDB1 Pro1067del. Furthermore, a complex duplication spanning the MECP2 gene was identified in two brothers who presented with developmental delay and intellectual disability. From our studies, we provide the first examples of autistic patients carrying potentially detrimental alterations in MBD6 and SETDB1, thereby demonstrating that the MBD gene family potentially plays a significant role in rare and private genetic causes of autism.

Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND)

“…18 MBD5 variants MBD5-specific variants have been identified in a cohort of autism cases that also exhibit the phenotype of 2q23.1 deletion syndrome, including ID, severe speech impairment, seizures, and autistic-like behavioral problems (see Supplementary Table 1 for list of published MBD5 variants likely to affect function, GenBank accession numbers: NM_018328.4, and NP_060798.2). 2,7,15,[19][20][21][22] Variants were submitted to http://www.ncbi.nlm.nih.gov/clinvar/?term = MBD5[gene]). The identification of mutations in MBD5 in individuals with significantly overlapping features verified that MBD5 was the critical gene responsible for the core features of 2q23.1 deletion syndrome.…”

Tagging Methyl-CpG-Binding Domain Proteins Reveals Different Spatiotemporal Expression and Supports Distinct Functions

“…Because Mbd2 -/-mice show these phenotypes in the absence of additional changes in behavior or monoamine signaling, we conclude that they are not neuronal in origin and that the absence of MBD2 does not significantly impact neuronal functions. These findings are surprising in the context of the other MBD family proteins, which have been linked to brain-related functions in humans and mice [25,26,28,29,32,33].…”

“…Genetic studies of MBD proteins in humans and animal models have demonstrated a critical role for this protein family in the brain [22,[25][26][27][28][29]. Mutations in several MBD proteins have been identified in individuals with autism spectrum disorder (ASD), although further work is needed to determine if these mutations are causative [25,26].…”

“…Mutations in several MBD proteins have been identified in individuals with autism spectrum disorder (ASD), although further work is needed to determine if these mutations are causative [25,26]. MeCP2 and MBD5 in particular are linked to the specific neurological diseases Rett syndrome and 2q23.1 microdeletion syndrome, respectively [27,30], both of which are closely recapitulated in mouse models with deletion or mutation of each gene [31,32].…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Rare variants in CHD7 are thought to confer increased autism risk, even in the absence of a CHARGE syndrome diagnosis [89]. Further still, mutations in genes highly related to MECP2, such as MBD5, have been found in idiopathic autism [90].…”