Mayo Sonia, Monfort Sandra, Roselló Mónica, Orellana Carmen, Oltra Silvestre, Caro-Llopis Alfonso, Martínez Francisco
Unidad de Genética, Hospital Universitario y Politécnico La Fe, Avenida de Fernando Abril Martorell 106, 46026 Valencia, Spain.
Int J Genomics. 2017;2017:4798474. doi: 10.1155/2017/4798474. Epub 2017 May 24.
We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All the genes forming these fusion transcripts may have an important role in central nervous system development and/or in gene expression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contribute to 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 deregulated expression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effect due to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in other pathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusion transcripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients with intellectual disability.
我们报告了三名患有智力残疾且携带导致三个新嵌合基因的拷贝数变异（CNV）的非亲缘患者。形成这些融合转录本的所有基因可能在中枢神经系统发育和/或基因表达调控中发挥重要作用，因此不仅它们的缺失或重复，而且由此产生的嵌合基因都可能导致患者的表型。当影响剂量敏感基因时，缺失和重复通常具有致病性。另外，嵌合基因也可能通过不限于剂量敏感基因的不同功能获得机制而致病：新多肽的出现，其结合了来自两个不同基因的功能域；相邻基因启动子区域对任何编码序列的表达失调；和/或由于部分截短蛋白功能域的保留而产生的假定显性负效应。融合致癌基因是众所周知的，但在其他病理学中，对嵌合基因的寻找却被忽视。根据我们的发现，我们推测融合转录本的频率可能比预期的要高得多，在智力残疾患者的阵列比较基因组杂交（array-CGH）分析中应予以考虑。
