Abstract： Objective:To explore the clinical features and genotypes of Cornelia de Lange Syndrome (CdLS) in neonates, and to provide a basis for clinical identification and diagnosis of CdLS.Methods:A retrospective analysis was conducted on six newborn CdLS children admitted to the Guangzhou Women and Children's Medical Center from January 2018 to December 2022. The demographic information, age of onset and diagnosis, prenatal diagnosis information, clinical manifestations, and other data of the patients were collected through the electronic medical record system. The children were scored according to the clinical diagnostic criteria and genetic diagnosis provided by the 2018 International Expert Consensus on the Diagnosis and Management of Cornelia de Lange Syndrome. Whole-exome sequencing was performed on the children, and the gene mutations were verified by Sanger sequencing of the parents. The prognosis of the children were assessed through outpatient and telephone follow-up. At the same time, relevant literature reviews were conducted.Results:Among these six children, one was male and five were female, all of whom were diagnosed in the neonatal period. Four patients had typical facial features, including arched eyebrows and (or) bushy eyebrows, short nose, concave nasal bridge and (or) forward-leaning nostrils, long philtrum and (or) flat philtrum, thin upper lip and (or) downturned corners of the mouth, microcephaly, and hirsutism. Additionally, one child had Cri du Chat syndrome, while another child presented with obstructive jaundice as the main manifestation. The clinical manifestations of the other two children were not typical, and CdLS was confirmed through genetic analysis. Among them, genetic diagnosis was completed for four patients, with two of NIPBL gene mutation and two of HDAC8 gene mutation. Among the 6 children, one died of respiratory failure after giving up treatment and removing the tracheal tube in the hospital, three died after discharge, one was lost to follow-up, and only one was discharged and followed up irregularly at our hospital's outpatient department. The child is currently 3 years and 3 months old and is experiencing growth retardation.Conclusion:The typical clinical presentation of CdLS in newborns includes distinctive facial features and multiple organ system malformations, which can be identified through typical clinical characteristics and confirmed by genetic analysis. It is important for clinical practitioners to understand the clinical features and genetic phenotype of CdLS and to facilitate early diagnosis and management.