Epigenome-wide profiling of trisomy 18 specific DNA methylation signatures in first-trimester chorionic villi

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BACKGROUND: Trisomy 18 (T18, Edwards syndrome) is a lethal chromosomal disorder characterized by multiple congenital anomalies and high perinatal mortality. Although epigenetic alterations have been described in aneuploidy conditions, their causal role in the pathogenesis of T18 remains unclear. This study aimed to characterize genome-wide DNA methylation changes associated with T18 during early development. MATERIAL AND METHODS: Genomic DNA was extracted from chorionic villi of five T18 and five euploid fetuses, as well as from normal maternal blood, at 11-13 weeks of gestation. High-resolution methyl-capture sequencing (MC-seq) was performed to profile DNA methylation at approximately 3.2 million CpG sites. Differentially methylated CpG sites (DMCs) and regions (DMRs) were identified. Functional and disease-association enrichment analyses were conducted using multiple bioinformatics tools. RESULTS: A global trend of DNA hypermethylation was observed in the chorionic villi of T18 fetuses. A total of 6,510 DMCs were identified, including 4,022 hypermethylated and 2,488 hypomethylated CpG sites. Additionally, 301 DMRs were identified, comprising 233 hypermethylated and 68 hypomethylated regions. Notably, chromosome 18, the disease-causing chromosome, contained the highest number of hypermethylated DMRs. Functional enrichment analysis of the 283 genes, including 301 DMRs, revealed significant involvement in biological processes and disease phenotypes relevant to T18, including nervous system development, anatomical structure morphogenesis, and embryonic morphogenesis (adjusted P < 0.001 for all). Among them, 76 DMRs exhibited completely inverse methylation patterns in maternal blood and were identified as potential epigenetic biomarkers for non-invasive prenatal testing of T18. CONCLUSIONS: To our knowledge, this is the first comprehensive MC-seq-based analysis of T18-specific DNA methylation patterns in first-trimester chorionic villi. These findings suggest that DNA methylation changes may represent downstream consequences of chromosomal imbalance in T18 and provide a foundation for future investigations into its pathophysiology and the development of epigenetic biomarkers for early non-invasive detection.

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