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bioRxiv · 10.64898/2026.10.20.760549

Early Prenatal Cell-Free DNA Methylation Landscape Informs Epigenetic Purification of the Circulating Fetal Genome

Liao, T.·Rao, C.·Iyer, S.·Ding, S. C.·Yu, J.·Lui, Z.·Yang, C.·Gu, W.
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Abstract

Circulating fetal cfDNA is the analyte of a screening test used by millions of pregnant women annually. However, low fetal fraction limits current testing. Fetal cfDNA can be enriched via hypomethylation, but the informative sites require a first-trimester fetal methylome reference. Here we sequenced fetal cfDNA (median purity 94.7%) derived from discarded media from cultured chorionic villus biopsies (n=30) and assembled a first-trimester methylome across 26M CpG methylation sites at a median depth of 207x. We then built an analytical enrichment model that identified millions of CpG markers and assigned predicted enrichment scores. Guided by this model, we adapted epiSIFT as a genome-wide assay selective for unmethylated DNA molecules. In 28 prenatal plasma cases, epiSIFT raised the median fetal fraction from 5.1% to 28.4% (5.6-fold gain) using the top eighth of markers. These findings establish a first-trimester fetal cfDNA methylome reference and demonstrate epigenetic enrichment of the fetal genome.

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Liao, T., Rao, C., Iyer, S., Ding, S. C., Yu, J., Lui, Z., Yang, C., Gu, W.. 2026-10-25. Early Prenatal Cell-Free DNA Methylation Landscape Informs Epigenetic Purification of the Circulating Fetal Genome. https://doi.org/10.64898/2026.10.20.760549

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