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

Authors

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

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 26 Oct 2026.

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