Chimeric Genes in Deletions and Duplications Associated with Intellectual Disability

摘要

We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All thegenes forming these fusion transcripts may have an important role in central nervous system development and/or in geneexpression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contributeto the phenotype of the patients. Deletions and duplications are usually pathogenic when affecting dose-sensitive genes.Alternatively, a chimeric gene may also be pathogenic by different gain-of-function mechanisms that are not restricted to dose-sensitive genes: the emergence of a new polypeptide that combines functional domains from two different genes, the deregulatedexpression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effectdue to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in otherpathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusiontranscripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients withintellectual disability.