Whole-genome resequencing with multidimensional annotation revealed pathogenic networks in sirenomelia

BACKGROUND: Sirenomelia is a rare and lethal congenital malformation representing the most severe form of caudal dysgenesis, with a stillbirth rate of up to 53%. The genetic basis of sirenomelia remains poorly understood. Consequently, in this study, we aimed to comprehensively characterize genomic variants and explore potential pathogenic mechanisms in sirenomelia. METHODS: Whole-genome resequencing was performed on peripheral blood mononuclear cells from one patient with sirenomelia and one matched healthy newborn. Variants were identified and prioritized using the gnomAD and ClinVar population databases. single nucleotide polymorphisms (SNP)/InDel and structural variants were further analyzed using multidimensional functional enrichment approaches. RESULTS: A total of 116 candidate genes harboring rare and potentially deleterious SNP/InDel variants were identified, including BMP5 and BMP6. Structural variant analysis revealed 549 sirenomelia-specific variants involving genes such as TWSG1 and Retinoic acid receptor beta (RARB). Functional enrichment revealed that these genes were predominantly involved in key developmental pathways, including BMP, WNT and TGF-β signaling. Integrated analysis indicated convergent disruption of signaling networks regulating posterior axis development, particularly those associated with kidney formation, cloacal partitioning, and limb patterning. CONCLUSION: These findings support a multilayered pathogenic model in which genetic variants collectively disrupt the core developmental pathways involved in posterior axis formation, vasculogenesis, and organogenesis. Our findings provide a genomic framework for understanding the molecular basis of sirenomelia and identify potential targets for future research and clinical applications.