The Expanding Role of the Methyl-CpG-Binding Domain Family In Autism Etiology

Background:  The methyl-CpG-binding domain (MBD) family performs a strategic role in epigenetic regulation by encoding for proteins involved in histone methylation and chromatin remodeling. The MBD genes have been linked to autism for over a decade ever since Rett syndrome, which falls under the umbrella of autism spectrum disorders (ASDs), was revealed to be caused by mutations in the MECP2 (methyl-CpG binding protein 2) gene. Since that time, a few classic autistic patients have been shown to carry alterations in MECP2 as well. Recent reports also demonstrate that patients with deletions across the MBD5 gene present clinically with intellectual difficulties, impaired speech, repetitive behaviors and seizures, all features found in ASD patients. Previous work in our laboratory investigating ASD patients identified variants in MECP2, MBD1, MBD2, MBD3 and MBD4 that altered amino acid sequence, were unique to autistic patients and concordant with disease in multiplex families.

Objectives:  We now describe the first study evaluating ASD individuals in four of the remaining MBD family members, MBD5, MBD6, SETDB1 (SET domain, bifurcated 1) and SETDB2, and expand our initial screening of patients in the MECP2 gene.

Methods:  All sixty-nine coding exons of these five MBD genes were Sanger sequenced in 576 samples (288 ASD individuals, 86 African American and 202 Caucasian, as well as 288 controls of matching ethnicity).

Results:  We identified a total of 144 alterations, the vast majority of which were novel (108 variants, 75%). Thirty-four of these alterations appear to result in a change in amino acid sequence, including thirty-one missense variations, two nonsense mutations, and a frameshift predicted to result from a single base pair insertion. In relation to the relatively small coding sequence of MECP2, this gene appears to carry a disproportionately large number of nonsynonymous alterations (10 variants, 29%). Thirty-two of the alterations identified are specific to ASD patients and absent in controls. It also appears that many of the variants are specific to a particular ethnicity, with 34 variants identified only in African Americans and 55 variants solely identified in Caucasians. We are currently sequencing additional family members in order to distinguish whether the variants segregate with disease.

Conclusions:  From our studies, we demonstrate that the MBD gene family may play a larger role in rare and private genetic causes of autism than was initially believed.