PDF(Pubmed)
Abstract：
The sheer number of gene variants and the extent of the observed clinical and molecular heterogeneity recorded in neuropsychiatric disorders (NPDs) could be due to the magnified downstream effects initiated by a smaller group of genomic higher-order alterations in response to endogenous or environmental stress. Chromosomal common fragile sites (CFS) are functionally linked with microRNAs, gene copy number variants (CNVs), sub-microscopic deletions and duplications of DNA, rare single-nucleotide variants (SNVs/SNPs), and small insertions/deletions (indels), as well as chromosomal translocations, gene duplications, altered methylation, microRNA and L1 transposon activity, and 3-D chromosomal topology characteristics. These genomic structural features have been linked with various NPDs in mostly isolated reports and have usually only been viewed as areas harboring potential candidate genes of interest. The suggestion to use a higher level entry point (the \'fragilome\' and associated features) activated by a central mechanism (\'stress\') for studying NPD genetics has the potential to unify the existing vast number of different observations in this field. This approach may explain the continuum of gene findings distributed between affected and unaffected individuals, the clustering of NPD phenotypes and overlapping comorbidities, the extensive clinical and molecular heterogeneity, and the association with certain other medical disorders.
摘要：
在神经精神疾病（NPD）中记录的基因变体的绝对数量以及观察到的临床和分子异质性的程度可能是由于较小的一组基因组高阶改变对内源性或环境的反应引起的放大的下游效应压力。染色体常见脆性位点（CFS）与microRNAs功能相关，基因拷贝数变异（CNVs），DNA的亚显微缺失和复制，罕见的单核苷酸变异（SNV/SNPs），和小插入/删除(indel)，以及染色体易位，基因重复，甲基化改变，microRNA和L1转座子活性，和3-D染色体拓扑特征。这些基因组结构特征已与大多数分离的报告中的各种NPD相关联,并且通常仅被视为具有潜在的感兴趣的候选基因的区域。建议使用由中央机制（“压力”）激活的更高级别的入口点（“脆弱性”和相关特征）来研究NPD遗传学，有可能统一该领域现有的大量不同观察结果。这种方法可以解释分布在受影响和未受影响的个体之间的基因发现的连续性，NPD表型和重叠合并症的聚类，广泛的临床和分子异质性，以及与某些其他医学疾病的联系。
