Cao Ye, Luk Ho Ming, Zhang Yanyan, Chau Matthew Hoi Kin, Xue Shuwen, Cheng Shirley S W, Li Albert Martin, Chong Josephine S C, Leung Tak Yeung, Dong Zirui, Choy Kwong Wai, Lo Ivan Fai Man
Department of Paediatrics, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong SAR, China.
Front Genet. 2022 Apr 14;13:803088. doi: 10.3389/fgene.2022.803088. eCollection 2022.
Structural variations (SVs) are various types of the genomic rearrangements encompassing at least 50 nucleotides. These include unbalanced gains or losses of DNA segments (copy number changes, CNVs), balanced rearrangements (such as inversion or translocations), and complex combinations of several distinct rearrangements. SVs are known to play a significant role in contributing to human genomic disorders by disrupting the protein-coding genes or the interaction(s) with cis-regulatory elements. Recently, different types of genome sequencing-based tests have been introduced in detecting various types of SVs other than CNVs and regions with absence of heterozygosity (AOH) with clinical significance. In this study, we applied the mate-pair low pass (∼4X) genome sequencing with large DNA-insert (∼5 kb) in a cohort of 100 patients with neurodevelopmental disorders who did not receive informative results from a routine CNV investigation. Read-depth-based CNV analysis and chimeric-read-pairs analysis were used for CNV and SV analyses. The region of AOH was indicated by a simultaneous decrease in the rate of heterozygous SNVs and increase in the rate of homozygous SNVs. First, we reexamined the 25 previously reported CNVs among 24 cases in this cohort. The boundaries of these twenty-five CNVs including 15 duplications and 10 deletions detected were consistent with the ones indicated by the chimeric-read-pairs analysis, while the location and orientation were determined in 80% of duplications (12/15). Particularly, one duplication was involved in complex rearrangements. In addition, among all the 100 cases, 10% of them were detected with rare or complex SVs (>10 Kb), and 3% were with multiple AOH (≥5 Mb) locating in imprinting chromosomes identified. In particular, one patient with an overall value of 214.5 Mb of AOH identified on 13 autosomal chromosomes suspected parental consanguinity. In this study, mate-pair low-pass GS resolved a significant proportion of CNVs with inconclusive significance, and detected additional SVs and regions of AOH in patients with undiagnostic neurodevelopmental disorders. This approach complements the first-tier CNV analysis for NDDs, not only by increasing the resolution of CNV detection but also by enhancing the characterization of SVs and the discovery of potential causative regions (or genes) contributory to could be complex in composition NDDs.
结构变异（SVs）是各种类型的基因组重排，包含至少50个核苷酸。这些包括DNA片段的不平衡增减（拷贝数变化，CNVs）、平衡重排（如倒位或易位）以及几种不同重排的复杂组合。已知SVs通过破坏蛋白质编码基因或与顺式调控元件的相互作用，在导致人类基因组疾病中起重要作用。最近，除了具有临床意义的CNVs和纯合缺失（AOH）区域外，还引入了不同类型的基于基因组测序的检测方法来检测各种类型的SVs。在本研究中，我们对100例神经发育障碍患者进行了大DNA插入片段（约5 kb）的配对末端低深度（约4X）基因组测序，这些患者在常规CNV检测中未得到有意义的结果。基于读取深度的CNV分析和嵌合读取对分析用于CNV和SV分析。AOH区域通过杂合单核苷酸变异（SNVs）率同时降低和纯合SNVs率升高来指示。首先，我们重新检查了该队列中24例患者先前报告的25个CNVs。检测到的这25个CNVs（包括15个重复和10个缺失）的边界与嵌合读取对分析所指示的边界一致，而位置和方向在80%的重复（12/15）中得以确定。特别地，一个重复涉及复杂重排。此外，在所有100例患者中，10%检测到罕见或复杂的SVs（>10 Kb），3%检测到多个AOH（≥5 Mb）位于已鉴定的印记染色体上。特别地，一名患者在13条常染色体上鉴定出AOH总值为214.5 Mb，怀疑存在父母近亲关系。在本研究中，配对末端低深度基因组测序解决了很大一部分意义不明确的CNVs，并在未确诊的神经发育障碍患者中检测到额外的SVs和AOH区域。这种方法不仅通过提高CNV检测的分辨率，还通过增强SVs的特征描述以及发现可能导致复杂组成的神经发育障碍的潜在致病区域（或基因），对神经发育障碍（NDDs）的一线CNV分析起到补充作用。
