Abstract：
Chromosomal structural variations (SVs) are a main cause of human genetic disease. Currently, karyotype, chromosomal microarray analysis (CMA), and fluorescent in situ hybridization (FISH) form the backbone of current routine diagnostics (CRD). These methods have their own limitations. CRD cannot identify cryptic balanced SVs and complex SVs even if these techniques were performed either simultaneously or in a sequential manner. Optical genome mapping (OGM) is a novel technology that can identify several classes of SVs with higher resolution, but studies on the applicability of OGM and its comparison with CRD are inadequate for difficult and complicated chromosomal SVs are lacking. Herein, seven patients with definite complicated SVs involving at least two breakpoints (BPs) were recruited for this study. The results of BPs and SVs from OGM were compared with those from CRD. The results showed that all BPs of five samples and partial BPs of two samples were detected by OGM. The undetected BPs were all close to the repeat-rich gap region. Besides, OGM also detected additional SVs including a cryptic balanced translocation, two additional complex chromosomal rearrangement (CCR). OGM yielded the additional information, such as the orientation of acentric fragments, BP positions, and genes mapped in the BP region for all the cases. The accuracy of additional SVs and BPs detected by OGM was verified by FISH panel and next-generation sequencing and Sanger sequencing. Taken together, OGM exhibit a better performance in detecting chromosomal SVs compared to the CRD. We suggested that OGM method should be utilized in the clinical examination to improve the efficiency and accuracy of genetic disease diagnosis, supplemented by FISH or karyotyping to compensate for the SVs in the repeat-rich gap region if necessary.
摘要：
染色体结构变异(SVs)是人类遗传疾病的主要病因。目前,核型,染色体微阵列分析（CMA），和荧光原位杂交（FISH）形成了当前常规诊断（CRD）的骨架。这些方法有其自身的局限性。即使同时或以顺序方式执行这些技术，CRD也无法识别隐秘的平衡SV和复杂SV。光学基因组作图（OGM）是一种新颖的技术，可以识别几类具有更高分辨率的SV，但是，对于困难和复杂的染色体SV，缺乏关于OGM适用性及其与CRD的比较的研究还不够。在这里，本研究招募了7例明确复杂的SVs患者,这些SVs包含至少2个断点(BPs).将OGM的BP和SV的结果与CRD的结果进行了比较。结果表明，OGM检测到5个样品的所有BPs和2个样品的部分BPs。未检测到的BP都接近富含重复的间隙区域。此外,OGM还检测到额外的SV，包括神秘的平衡易位，两个额外的复杂染色体重排（CCR）。OGM产生了额外的信息，比如无心碎片的方向，BP头寸，以及所有病例在BP区域定位的基因。通过FISH面板和下一代测序和Sanger测序验证了通过OGM检测的其他SV和BPs的准确性。一起来看,与CRD相比，OGM在检测染色体SV方面表现出更好的性能。我们建议在临床检查中使用OGM方法，以提高遗传病诊断的效率和准确性。补充FISH或核型分析，以补偿富含重复序列的间隙区域中的SV。
