Genome Sequencing Explores Complexity of Chromosomal Abnormalities in Recurrent Miscarriage
Genome Sequencing Explores Complexity of Chromosomal Abnormalities in Recurrent Miscarriage
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DOI：
10.1016/j.ajhg.2019.10.003
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发表时间：
2019-12-05
影响因子：
9.8
通讯作者：
Chen, Zi-Jiang
中科院分区：
文献类型：
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作者：
Dong, Zirui;Yan, Junhao;Chen, Zi-Jiang
复发性流产(RM)影响全球数百万夫妇，其中一半没有明确的病因。基因组测序(GS)是一种增强的、新的细胞遗传学工具，用于确定染色体异常在人类疾病中的作用。在这项研究中，我们评估了它在受RM影响的夫妇中的有效性。我们对1,090对受RM影响的夫妇进行了回顾性的低通GS检查，所有这些夫妇都进行了常规的染色体分析。开发了一种定制的测序和解释管道，用于识别染色体重排和缺失/复制，并通过荧光原位杂交、染色体微阵列分析和聚合酶链式反应研究进行确认。1,090对夫妇中有1,077对(98.8%)获得了低通GS检测结果，在11.7%(126/1,077对)夫妇中检测到127条染色体异常；其中一对夫妇的两个成员都被确认为倒位。在126对夫妇中，39.7%(50/126)的夫妇根据正常男性或女性的核型特征获得了先前的诊断结果。低通GS在50对(4.0%)夫妇中发现了额外的染色体异常，包括8对平衡易位和42对倒位。对这些夫妇的跟踪研究显示，与GS正常的夫妇中的21/93(22.6%)相比，这些夫妇的流产/胎儿异常发生率更高，为5/10(50%)，导致相对风险为2.2(95%可信区间，1.1至4.6)。在这些夫妇中，与染色体分析(8.0%，卡方检验p=0.000751)相比，这种方法显著提高了每对夫妇的染色体异常诊断率(11.7%)。总而言之，低通GS在9对受RM影响的夫妇中发现了1对潜在的染色体异常，从而能够识别出随后流产风险增加的一组夫妇，他们将从个性化干预中受益。
Recurrent miscarriage (RM) affects millions of couples globally, and half of them have no demonstrated etiology. Genome sequencing (GS) is an enhanced and novel cytogenetic tool to define the contribution of chromosomal abnormalities in human diseases. In this study we evaluated its utility in RM-affected couples. We performed low-pass GS retrospectively for 1,090 RM-affected couples, all of whom had routine chromosome analysis. A customized sequencing and interpretation pipeline was developed to identify chromosomal rearrangements and deletions/duplications with confirmation by fluorescence in situ hybridization, chromosomal microarray analysis, and PCR studies. Low-pass GS yielded results in 1,077 of 1,090 couples (98.8%) and detected 127 chromosomal abnormalities in 11.7% (126/1,077) of couples; both members of one couple were identified with inversions. Of the 126 couples, 39.7% (50/126) had received former diagnostic results by karyotyping characteristic of normal human male or female karyotypes. Low-pass GS revealed additional chromosomal abnormalities in 50 (4.0%) couples, including eight with balanced translocations and 42 inversions. Follow-up studies of these couples showed a higher miscarriage/fetal-anomaly rate of 5/10 (50%) compared to 21/93 (22.6%) in couples with normal GS, resulting in a relative risk of 2.2 (95% confidence interval, 1.1 to 4.6). In these couples, this protocol significantly increased the diagnostic yield of chromosomal abnormalities per couple (11.7%) in comparison to chromosome analysis (8.0%, chi-square test p = 0.000751). In summary, low-pass GS identified underlying chromosomal aberrations in 1 in 9 RM-affected couples, enabling identification of a subgroup of couples with increased risk of subsequent miscarriage who would benefit from a personalized intervention.