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Diagnostic yield of trio exome sequencing as a first-tier test for identifying genetic causes of pregnancy loss

Journal of Human Genetics volume 70, pages 517–527 (2025)Cite this article

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Abstract

Genetic defects are a major cause of pregnancy loss, leading to fetal death or elective abortion due to congenital anomalies. This study evaluates the effectiveness of trio exome sequencing (ES) in identifying genetic causes of pregnancy loss. Trio ES was used as a first-tier genetic test on 193 cases of pregnancy loss to detect both chromosomal abnormalities and small variants potentially linked to fetal death and anomalies. The pathogenicity of identified variants was assessed, and the diagnostic yield was analyzed. Trio ES provided an overall diagnostic yield of 24% (47/193) across this cohort, with a similar positive rate observed in fetal death (26%, 12/45) and elective abortion (23%, 35/148) groups. Among diagnosed cases, 45% (21/47) were attributed to chromosomal abnormalities, while 55% (26/47) were caused by small variants. This suggests that ES more than doubled the positive rates compared to traditional methods such as karyotyping and chromosomal microarray analysis. Notably, chromosomal abnormalities were the primary cause of fetal death (75%, 9/12), whereas small variants were more prevalent in elective abortion cases (68%, 24/35), particularly those with central nervous and skeletal anomalies. Additional candidate variants were identified in 35 inconclusive cases (18%), potentially further increasing the detection rate. This study highlights the value of trio ES in diagnosing genetic causes of pregnancy loss. Implementing it as a first-tier test can significantly enhance our understanding of fetal death and anomalies, therefore facilitating informed future pregnancy management.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was partly supported by a grant from the Science and Technology Program of Guangzhou, China (2024A03J0755). The authors are sincerely grateful to the patients and their families for participating in this study.

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Authors and Affiliations

  1. KingMed Diagnostics, Guangzhou, Guangdong, China

    Lina Xiang, Anqi Deng, Jie Zhou, Xuefan Dong, Wenbo Mu, Qi Zhang, Jing Zhang, Sha Tang, Ping Fang & Xiaoqiang Cai

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  1. Lina Xiang
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  2. Anqi Deng
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  3. Jie Zhou
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  10. Xiaoqiang Cai
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Contributions

Conceptualization: XC, LX, PF; Data Curation: LX, AD, XD, XC; Formal Analysis: LX, AD, QZ, JZ, ST, PF, XC; Methodology: XC, JZ, WM, QZ, JZ, ST; Writing-original draft: XC, LX, JZ, ST, PF; Writing-review and editing: all authors. All authors read and approved the final manuscript.

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Correspondence to Xiaoqiang Cai.

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The authors declare no competing interests.

Ethics approval

The research protocol was reviewed and approved by the Institutional Review Board of KingMed Diagnostics (No. 2024099). The study was conducted in accordance with the Declaration of Helsinki. A waiver of informed consent was granted by the Institutional Review Board in the study on the grounds that all data were fully deidentified and anonymized prior to analysis, the study posed no more than minimal risk to participants, and the exemption would not adversely affect the rights or welfare of the individuals involved.

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Xiang, L., Deng, A., Zhou, J. et al. Diagnostic yield of trio exome sequencing as a first-tier test for identifying genetic causes of pregnancy loss. J Hum Genet 70, 517–527 (2025). https://doi.org/10.1038/s10038-025-01373-7

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