Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

Abstract

The development of microarray-based technologies for comparative genomic hybridization (array-CGH) analysis has enabled the detection of submicroscopic microdeletions or microduplications, also referred to as copy number variations (CNVs). Recently, this approach has been widely used in neurologic and psychiatric disorders, including mental retardation (MR),^1-3 autism spectrum disorders (ASDs),^4-7 and schizophrenia.^8-11 Findings from these studies suggested that several genes involved in similar neurodevelopmental pathways may be associated with these conditions. However, so far only rare structural variants, sometimes present in a single case, have been identified. Therefore, it is difficult to decipher which of these variations are causative, which are risk factors, and which are only rare polymorphisms unrelated to any pathologic phenotype. De novo rearrangements are usually considered pathogenic, but this argument (which is acceptable for rare large rearrangements detectable by conventional cytogenetics) should be considered with caution for smaller CNVs, for which a high mutation rate is expected. Indeed, it has been estimated that a de novo segmental deletion occurs in 1 per 8 newborns and a de novo segmental duplication in 1 per 50 newborns, with most of these rearrangements being benign polymorphic variants.¹² Therefore, the disease association of CNVs has to be tested systematically by comparing the frequency of each candidate CNV in cases and in healthy control subjects. Given the low frequency of each CNV, this would require the study of huge series, achievable only in the context of forthcoming meta-analyses. Other problems arise because ascertainment of most of the published samples, initially recruited for linkage studies, is biased toward multiplex cases and because control samples, when present, are generally composed of subjects not screened for the studied pathologic conditions. The objectives of the present study were (1) to provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with controls and (2) to assess whether each CNV is present in more than 1 clinical category.