Cornelia de Lange syndrome （CdLS） is a rare genetic disorder characterized by multisystem developmental abnormalities， with its core pathogenic mechanism closely linked to dysfunction of the cohesin complex. Integrated multi‑omics evidence revealed that cohesin dysfunction disrupted three‑dimensional chromatin architecture and epigenetic homeostasis， triggered genome‑wide transcriptional dysregulation， and perturbed the regulatory networks of signaling pathways such as Wnt/β‑catenin， TGF‑β/BMP， and Sonic Hedgehog （SHH）. These disturbances collectively drove multisystem phenotypes involving the neurological， cardiovascular and skeletal systems， and laid a theoretical foundation for further understanding of the pathological mechanisms of CdLS and optimizing molecular diagnosis. This review summarized the genetic basis （including epigenetic dysregulation mechanisms） and disruption of key developmental signaling pathways in CdLS，and discussed strategies for optimizing molecular diagnosis.