Hypothesis: Dysregulation of methylation of brain-expressed genes on the X chromosome and autism spectrum disorders

The hypothesis is set forth that dysregulation of brain‐expressed genes on the X chromosome constitutes the major predisposition to autism spectrum disorders (ASDs). This dysregulation, mediated by hypomethylation or hypermethylation of CpG sites within gene promoters, leads to overexpression or partial silencing of one or more brain‐expressed genes, which in turn results in an unbalanced production of the proteins responsible for brain structure and function. This hypothesis accommodates the predominantly sporadic occurrence (95%), the male excess (4:1), and the usual absence of malformations or other syndromic manifestations in ASDs. © 2008 Wiley‐Liss, Inc.