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首页> 外文期刊>Molecular syndromology >Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements
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Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

机译：复杂染色体重排的起源机制，表型效应和诊断意义

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C (JMJD2C) as a novel candidate gene for mental retardation.
机译：复杂染色体重排（CCR）当前定义为结构基因组变异，涉及2个以上的染色体断裂并导致染色体区段的交换。人们认为它们极为罕见，但由于分子细胞遗传学技术的改进，其检测率正在提高。他们的人口频率也被低估了，因为许多CCR可能不会引起表型效应。 CCR可能是前叉失速和模板切换，微同源性介导的断裂诱导修复，断裂-融合-桥循环或染色体上裂的结果。染色体不稳定综合征患者显示减数分裂过程中DNA双链断裂反应受损，导致CCR发生率升高。因此，讨论了由ATM，BLM，WRN，ATR，MRE11，NBS1和RAD51编码的蛋白在预防CCR中的假定功能。 CCR可能通过（1）基因剂量依赖性机制（例如，单倍不足，（2）基于基因组结构破坏的机制，例如基因，基因的一部分或调节元件被截断，融合或重新定位，从而干扰了它们的相互作用-这些机制将主要影响基因表达-或（3）混合突变一种机制，其中一条染色体上的CCR与另一条染色体上的不同类型的突变结合在一起。这种推测的致病性机制需要通过mRNA测序加以证实。同样，未来对体外模型的研究，例如来自CCR患者的可诱导性多能干细胞以及转基因模型生物，应证实有关CCR假定致病作用的最新推论。关于临床和实验遗传学以及未来治疗方式的CCR信息日益增多的分支，仅用2例进行了简要说明，其中1例表明KDM4C（JMJD2C）是一种智力障碍的新型候选基因。

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