Phenotype-informed trio analysis reveals a multi-layered fetal genomic architecture in preterm birth
Abstract
Abstract Preterm birth remains incompletely explained, partly due to a limited understanding of how fetal genomic variation integrates with phenotype. We aimed to assess whether prematurely born neonates harbor distinct genomic signals reflecting fetal contribution to preterm birth (PTB) using an integrated analysis of relative fitness, inherited PTB-associated variants, de novo variants (DNVs), and quantitative phenotyping. We analyzed parent-offspring trios comprising 71 preterm cases (23 included in the final DNV analysis) and 25 term-born controls. Genomic data were generated using SNP arrays and short-read whole-genome sequencing, and variants were prioritized and analyzed for functional pathways. The relative fitness of variants was evaluated, and enrichment analysis was performed. A quantitative Major Neonatal Outcome (MNO) score was developed and used as a continuous phenotype in genotype–phenotype analyses. Preterm neonates (PN) and their mothers exhibited distinct rare variant profiles compared to term-born controls, with no overlap in curated PTB-associated loci. Relative fitness analysis revealed contrasting genomic signatures: term-born controls were enriched for rare or population-absent variants, whereas preterm genomes were dominated by more common non-coding variation. A total of 147 DNVs were identified across 23 PN, of which most were non-coding (74.3%). No strong association was observed between overall DNV burden and clinical severity. However,…
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