ENOrphanet Journal of Rare Diseases | Multi-omics analysis of multiple chorangioma in monochorionic twins reveals a multi-step pathological mechanism
Date: February 14, 2026
Classification: Frontiers
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This study performs whole-genome and transcriptome sequencing on a unique case of multiple chorangioma affecting only one twin in a monochorionic pregnancy with a shared placenta, proposing for the first time a molecular mechanism involving the interaction between germline and somatic variants, offering new insights into the interplay of genetic and environmental factors in placental vascular disorders.
Literature Overview
This article, 'Multi-omic analysis identifies a multi-step pathology in a case of multiple chorangioma syndrome in monochorionic twins,' published in the journal Orphanet Journal of Rare Diseases, reviews and summarizes a rare case of widespread multiple chorangiomas localized to the placental region of only one fetus in a monochorionic twin pregnancy with a shared placenta. Using whole-genome and transcriptome sequencing, the research team systematically analyzed genetic variations, mutational signatures, and gene expression differences between affected and unaffected placental tissues, revealing synergistic effects between germline variants in EPAS1 and somatic mutations in COL1A1, FBXO11, and TRIM71. A multi-step molecular model for multiple chorangioma development is proposed. This study provides the first direct molecular evidence for the pathogenesis of placental vascular abnormalities and suggests potential overlap with tumor-like molecular processes. The findings are significant for understanding fetal vascular perfusion abnormalities, preeclampsia, and intrauterine growth restriction.Background Knowledge
Chorangiomas are the most common benign vascular tumors of the placenta, occurring in approximately 1% of pregnancies, and are mostly solitary with no significant clinical consequences. However, multiple chorangioma syndrome is extremely rare and often leads to fetal heart failure, non-immune hydrops, or even intrauterine fetal demise, with mechanisms remaining unclear. Although prior studies suggest hypoxia and the VEGF signaling pathway may be involved in their development, direct molecular evidence has been lacking. Monochorionic twins, especially monochorionic diamniotic (MCDA) twins, provide an ideal model for studying localized placental lesions due to shared placentas, vascular anastomoses, and hemodynamic imbalances. In such twins, when only one placental region is affected, maternal systemic factors can be effectively excluded, allowing focused investigation of local molecular events. Recent advances in multi-omics technologies have provided new tools for dissecting clonal evolution and mutational signatures in complex diseases. However, degradation in placental tissues, especially formalin-fixed paraffin-embedded (FFPE) samples, poses challenges for high-quality sequencing. This study overcomes these technical hurdles by combining WGS and RNA-Seq, systematically revealing the molecular basis of multiple chorangiomas, filling a gap in understanding their genetic mechanisms, and offering new directions for precise diagnosis and potential intervention in placental pathology.
Methods and Experiments
The study included a pair of monochorionic twins delivered by cesarean section at 35 weeks, with a shared placenta but extensive multiple chorangiomas localized to only the placental region of fetus A (affecting >90% of the parenchymal volume). Samples were collected from the chorangioma tissue, unaffected villous tissue from fetus A, normal villous tissue from fetus B, and maternal decidual tissue. Multi-omics analysis was performed using whole-genome sequencing (WGS) and bulk RNA sequencing (RNA-Seq). WGS data were aligned (BWA-MEM), subjected to variant calling (GATK Mutect2, Manta), and corrected for FFPE-induced artifacts, followed by annotation of germline and somatic variants (ACMG/AMP guidelines). Clonal evolution analysis was performed using PyClone-VI and ClonEvol. Mutational signature analysis was conducted using SigProfilerExtractor. RNA-Seq data were processed using nf-core pipelines, and differential expression analysis was performed using DESeq2. All analyses strictly controlled for quality and corrected for FFPE-induced false variants.Key Findings and Insights
Significance and Outlook
This study is the first to reveal the molecular pathogenesis of multiple chorangiomas at the molecular level, proposing a multi-step model in which germline EPAS1 variants serve as a genetic susceptibility basis, overlaid with somatic mutations in COL1A1, FBXO11, and TRIM71 driving localized vascular lesions. This finding not only provides potential molecular diagnostic markers for this rare syndrome but also expands our understanding of placental angiogenesis regulation. The study suggests that chorangiomas may not be entirely benign, as their molecular features overlap with tumors, such as oxidative stress and clonal evolution, providing a basis for re-evaluating their biological behavior.
Future studies should expand cohorts to validate the prevalence of EPAS1 and other gene variants and perform functional validation using in vitro trophoblast or endothelial cell models. Single-cell sequencing and spatial transcriptomics will help resolve cellular heterogeneity and spatial distribution within lesions. Additionally, this study highlights the value of the placenta as a 'natural chimera,' providing a unique model for studying the role of somatic mutations in development and disease. These findings have important implications for understanding the vascular pathologies of common pregnancy complications such as preeclampsia and fetal growth restriction.
Conclusion
This study, through multi-omics analysis of asymmetrically distributed multiple chorangiomas in monochorionic twins, reveals their molecular pathogenesis for the first time. It identifies a germline or early embryonic frameshift deletion in EPAS1 as a potential genetic susceptibility factor leading to dysregulated placental hypoxia response. On this background, the affected region acquires pathogenic somatic mutations in COL1A1, FBXO11, and TRIM71, driving localized abnormal vascular proliferation. Transcriptomic and mutational signature analyses further support the activation of oxidative stress and the Leptin signaling pathway. Clonal evolution analysis suggests a tumor-like clonal expansion during disease progression. These findings provide the first molecular model for multiple chorangiomas and reveal the complex interplay between genetic and environmental factors in placental pathology. The study underscores the placenta's unique value as a model for studying somatic mutations and clonal evolution, with broad implications for understanding pregnancy-related vascular disorders such as preeclampsia and fetal growth restriction. Although limited to a single case, the proposed molecular framework lays the foundation for future functional studies and potential intervention strategies.
