Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease.
Deciphering the pathogenic consequences of chromosomal aberrations in human genetic disease.
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DOI：
10.1186/s13039-014-0100-9
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发表时间：
2014
影响因子：
1.3
通讯作者：
Hochstenbach R
中科院分区：
文献类型：
--
作者：
Kloosterman WP;Hochstenbach R
染色体畸变包括易位、缺失、重复、倒位、非整倍体和复杂的重排。大约15%的多发性先天性异常和/或智力低下（MCA/MR）患者是遗传疾病的基础。在遗传诊断中，这些患者的染色体畸变的致病性通常是根据与其他具有相同或重叠畸变的患者的表型相似性、健康个体的缺失、新生发生和蛋白质编码基因含量等标准来评估的。然而，由于染色体畸变导致MCA/MR的分子机制往往缺乏透彻的理解。染色体畸变可以以复杂的方式影响一个或多个基因，例如通过改变基因表达的调节，通过破坏外显子，以及通过产生融合基因。通过全基因组测序对断点的精确描述，可以构建局部基因组结构，并有助于预测患者表型的分子决定因素。在这里，我们回顾了目前的断点鉴定方法及其对MCA/MR患者染色体畸变解释的影响。此外，我们还讨论了基于大规模基因组技术和模式生物研究来剖析疾病机制的机会。本文的在线版本（doi:10.1186/s13039-014-0100-9）包含补充材料，仅供授权用户使用。
Chromosomal aberrations include translocations, deletions, duplications, inversions, aneuploidies and complex rearrangements. They underlie genetic disease in roughly 15% of patients with multiple congenital abnormalities and/or mental retardation (MCA/MR). In genetic diagnostics, the pathogenicity of chromosomal aberrations in these patients is typically assessed based on criteria such as phenotypic similarity to other patients with the same or overlapping aberration, absence in healthy individuals, de novo occurrence, and protein coding gene content. However, a thorough understanding of the molecular mechanisms that lead to MCA/MR as a result of chromosome aberrations is often lacking. Chromosome aberrations can affect one or more genes in a complex manner, such as by changing the regulation of gene expression, by disrupting exons, and by creating fusion genes. The precise delineation of breakpoints by whole-genome sequencing enables the construction of local genomic architecture and facilitates the prediction of the molecular determinants of the patient’s phenotype. Here, we review current methods for breakpoint identification and their impact on the interpretation of chromosome aberrations in patients with MCA/MR. In addition, we discuss opportunities to dissect disease mechanisms based on large-scale genomic technologies and studies in model organisms. The online version of this article (doi:10.1186/s13039-014-0100-9) contains supplementary material, which is available to authorized users.
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