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.

中文翻译：

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基因组测序探讨了反复流产中染色体异常的复杂性。

复发性流产（RM）影响全球数以百万计的夫妻，其中一半没有病因证明。基因组测序（GS）是一种增强的新型细胞遗传学工具，用于定义人类疾病中染色体异常的贡献。在这项研究中，我们评估了其在受RM影响的夫妇中的效用。我们对1090例受RM影响的夫妇进行了低通GS回顾性研究，他们都进行了常规染色体分析。开发了定制的测序和解释流程，以通过荧光原位杂交，染色体微阵列分析和PCR研究确认染色体重排和缺失/重复。低通GS在1,090对夫妇中有1,077个（98.8％）产生结果，在11.7％（126 / 1,077）对夫妇中检测到127个染色体异常。一对夫妇的两个成员均被识别为倒置。在这126对夫妇中，有39.7％（50/126）通过正常人的男性或女性核型的核型分析获得了先前的诊断结果。低通GS揭示了50对（4.0％）夫妇中的其他染色体异常，包括8个平衡平衡的易位和42个倒位。对这些夫妇的随访研究表明，GS正常的夫妇的流产/胎儿异常率更高，为5/10（50％），而21/93（22.6％）更高，导致相对风险为2.2（95％的置信度区间1.1到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，该方案显着提高了每对夫妇的染色体异常的诊断率（11.7％）。总之，