Early-onset severe preeclampsia (EO-PE) is a distinct and highly consequential form of preeclampsia (PE), presenting significant challenges for early detection. Here, we investigated the fragmentation pattern of plasma cell-free DNA (cfDNA) in EO-PE patients. We uncovered that the nucleotide composition at the 5' end (i.e. ends motif) of plasma cfDNA showed a unique pathological preference in EO-PE pregnancies and gestational-psychology preference in healthy pregnancies. By integrating 91 EO-PE specific motifs into a machine-learning model, we achieved accurate prediction of EO-PE development in early pregnancies. Remarkably, our model demonstrated robust performance in an independent cohort of 74 early pregnancies and 1,241 non-invasive prenatal testing (NIPT) samples with ultra-low sequencing depth. Additionally, we revealed that these PE-specific motif signatures lacked tissue specificity, originating extracellularly, and were associated with the abnormal concentration of DNA fragmentation factor subunit beta (DFFB) in EO-PE patients' plasma. These findings establish the plasma DNA fragmentome as a non-invasive and cost-effective biomarker that can be simultaneously captured during NIPT for early EO-PE detection and provide valuable insights into cfDNA production mechanisms in preeclampsia patients.

中文翻译：

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利用游离DNA片段组检测早发型重度子痫前期

早发性重度子痫前期 (EO-PE) 是子痫前期 (PE) 的一种独特且后果严重的形式，对早期检测提出了重大挑战。在这里，我们研究了 EO-PE 患者血浆游离 DNA (cfDNA) 的碎片模式。我们发现，血浆 cfDNA 5' 端（即末端基序）的核苷酸组成在 EO-PE 妊娠中表现出独特的病理学偏好，在健康妊娠中表现出妊娠心理偏好。通过将 91 个 EO-PE 特定主题整合到机器学习模型中，我们实现了妊娠早期 EO-PE 发育的准确预测。值得注意的是，我们的模型在由 74 名早期妊娠和 1,241 份具有超低测序深度的无创产前检测 (NIPT) 样本组成的独立队列中表现出了稳健的性能。此外，我们发现这些 PE 特异性基序特征缺乏组织特异性，起源于细胞外，并且与 EO-PE 患者血浆中 DNA 碎片因子亚基β (DFFB) 浓度异常有关。这些发现将血浆 DNA 片段组确立为一种非侵入性且经济有效的生物标志物，可以在 NIPT 期间同时捕获，用于早期 EO-PE 检测，并为先兆子痫患者的 cfDNA 产生机制提供有价值的见解。