Abstract
Non-invasive prenatal testing (NIPT) enables the screening of fetal chromosomal abnormalities by analyzing cell-free DNA (cfDNA) in maternal blood. Recent technological advancements have expanded its applications to the detection of copy number variations (CNVs). However, the clinical utility of CNV detection remains unclear. We aimed to investigate the association between fetal CNVs detected by genome-wide NIPT and perinatal outcomes in a large cohort in Japan. This retrospective cohort study included 46,082 patients who underwent NIPT at certified facilities in Japan between January 2015 and September 2021. Genome-wide NIPT was performed using massively parallel sequencing to detect fetal CNVs exceeding 7 Mb. Despite their small size, well-characterized microdeletions, such as 22q11.2 were included. From 46,082 patients with NIPT results, 30,373 cases with known birth outcomes were extracted, and cases with fetal CNV were included in the analysis. Fetal CNVs were detected in 66 patients (0.2%). Adverse outcomes, including miscarriage, growth restriction, and structural abnormalities, were observed in 14 of the 66 cases (21.2%). Pathogenic CNVs were frequently detected even in the 52 cases (78.8%) with favorable outcomes. Genome-wide NIPT may assist in the diagnosis of cases with structural abnormalities when combined with confirmatory testing. Our findings demonstrate that pathogenic CNVs are also detected in a substantial number of structurally normal fetuses with favorable short-term outcomes. This discordance presents a significant challenge for prenatal counseling. The clinical significance of the findings should be clarified through confirmatory testing of CNV cases and the accumulation of data from long-term follow-up studies.
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Acknowledgements
We thank Dr. Jun Murotsuki (formerly of the Department of Obstetrics and Gynecology, Miyagi Children’s Hospital) and Dr. Mika Ito (formerly of the Department of Obstetrics and Gynecology, Toyama University Hospital) for their valuable contributions in providing clinical data during the early phase of this study. We also would like to thank the clinical geneticists, counselors, and staff at all institutions that contributed to this study.
Funding
This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS KAKENHI), Grant Number 23K08810.
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Yuka Yamashita, Seiji Wada, Haruhiko Sago, Yuki Ito, Osamu Samura, Nobuhiro Suzumori, Hideaki Sawai, Yuko Tamaki, Yukiko Katagiri, Yoshiki Maeda, Hiroko Morisaki, Akira Namba, Yoshimasa Kamei, Junko Yotsumoto, Yuri Hasegawa, Kiyonori Miura, Setsuko Nakayama, and Akihiko Sekizawa conceptualized and designed the study. All co-authors were responsible for the acquisition and management of clinical data. Koshichi Goto performed the CNV analysis and interpreted the genetic findings. Yuka Yamashita and Akihiko sekizawa wrote the first draft of the manuscript. All co-authors critically reviewed and revised the manuscript. All authors read and approved the final manuscript.
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Yamashita, Y., Shirato, N., Ishii, T. et al. Perinatal outcomes of fetal CNVs detected by genome-wide non-invasive prenatal testing in Japan. J Hum Genet 71, 81–89 (2026). https://doi.org/10.1038/s10038-025-01409-y
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DOI: https://doi.org/10.1038/s10038-025-01409-y
