Whole-Genome Resequencing for Detection of Sirenomelia Gene Mutations
Sirenomelia is a rare and fatal congenital malformation representing the most severe form of tail hypoplasia, with a stillbirth rate as high as 53%. This study represents the first application of whole-genome resequencing to analyze peripheral blood samples from sirenomelia patients. It comprehensively covers both coding and non-coding regions, efficiently detects structural variations while minimizing technical biases, and addresses the limitations of whole-exome sequencing in identifying non-coding and structural variants. This approach provides more complete molecular evidence supporting the hypotheses of vascular steal and embryonic developmental defects in the pathogenesis of sirenomelia. Subsequently, multidimensional enrichment analysis (GO, KEGG, Reactome, DO) was performed on the SNP-Indel mutations and chromosomal structural variations identified through differential screening. This revealed dysregulation in lysosomal function and cellular metabolism, abnormalities in muscle structure and function, disruptions in hormone synthesis and metabolic processes, and alterations in signaling pathways and the extracellular matrix among sirenomelia patients. This study comprehensively elucidates the potential molecular mechanisms underlying sirenomelia, identifying key candidate SNPs (BMP5/BMP6, ENG, CREBBP, LMBRD1) and their mutation sites, along with multiple potential pathogenic chromosomal structural variations (WLS/WNT7B, GLI2, TGFBR3/ACVR1B, RARB, TWSG1). This provides a theoretical foundation for subsequent in-depth studies on its pathogenic mechanisms, prenatal diagnosis, and familial genetic risk assessment.