Multi-omic analysis identifies a multi-step pathology in a case of multiple chorangioma syndrome in monochorionic twins.

backgroundChorangiomas, benign capillary lesions of the placenta, occur in ~1% of births, typically as solitary nodules. Multiple chorangioma syndrome is rare and increases risk of fetal heart failure, hydrops fetalis, and intrauterine death due to placental hemodynamic disruption. While genetic and hypoxic factors have been suggested in chorangioma development, direct molecular evidence is lacking. Here, we present a unique case of multiple chorangiomas confined to half of a shared placenta in monozygotic monochorionic diamniotic twins, providing a rare opportunity to dissect molecular drivers of chorangioma formation.

methodsFormalin-fixed paraffin-embedded tissue samples from chorangioma, affected and unaffected villi, and decidua from MCDA twins were subjected to whole-genome and bulk RNA sequencing. Germline and somatic small, structural, and copy number variants were identified. Clonal evolution analysis was conducted using PyClone-VI and ClonEvol. Mutational signature profiling was performed with SigProfilerExtractor to characterize molecular drivers of pathology. RNA-Seq (100 M reads/sample) was processed using the nf-core RNA-Seq pipeline, with differential expression analysis via DESeq2 to identify transcriptomic changes and mutational signatures. Quality control and artifact filtering were applied to mitigate FFPE-induced sequencing errors.

resultsWe identified a likely pathogenic early embryonic or germline EPAS1 frameshift deletion, suggesting impaired placental oxygen regulation and VEGF-driven angiogenesis. Chorangioma-affected tissue harbored pathogenic COL1A1, FBXO11, and TRIM71 somatic mutations, with elevated Leptin expression and oxidative stress signatures. In contrast, the unaffected twin’s placental territory carried a pathogenic MUTYH variant and repair deficiency-associated mutational signatures. These findings reveal distinct molecular processes in each placental domain and suggest a predisposing genetic alteration.

conclusionsOur study provides novel insights into the molecular basis of multiple chorangioma syndrome. To our knowledge, it is the first study to propose a molecular mechanism and the first to propose interaction of germline and somatic variants in syndrome pathobiology. Identification of molecular signatures linked to malignancy suggests potential overlap with oncogenic pathways that, if confirmed, would extend understanding of placental biology. These findings highlight the genetic-environmental interplay in placental pathology, with implications for preeclampsia, intrauterine growth restriction, and fetal vascular malperfusion.