Background: Medulloblastoma (MB) is the most common intracranial malignant tumour in children, but genes and pathways involved in its pathogenesis are still under investigation. This study was designed to screen and identify biomarkers of MB to provide markers for clinical diagnosis and prognosis assessment. Methods: The data sets of GSE109401 and GSE42656 were acquired from Gene expression omnibus (GEO). Limma package in R was adopted to identify the differentially expressed genes (DEGs), and the GSE30074 data set was adopted to analyse their prognostic role. Children with MB (n=55) diagnosed in Affiliated Ezhou Central Hospital were enrolled and assigned to the patient group, and healthy children (n=30) who received physical examination in our hospital during the same time period were assigned to the control group. The two groups were compared in serum NLGN2 and PTGDS levels, and all patients were followed up for three years to understand the associations of Neuroligin 2 (NLGN2) and Prostaglandin D2 synthase (PTGDS) with the survival of patients. Results: With Limma, 247 DEGs were screened out. The LASSO Cox regression analysis revealed that 6 genes were associated with MB prognosis, and the established model revealed a lower survival rate in the high risk group. According to Cox regression analysis, NLGN2 and PTGDS may be independent prognostic factors of MB. Similar to the data sets, the Real time-quantitative polymerase chain reaction (RT-qPCR) assay revealed lowly-expressed NLGN2 and PTGDS levels in MB patients, and patients with lower expression of them showed a lower 3-year survival rate. Conclusion: With low expression in MB cases, NLGN2 and PTGDS have high prognostic value for MB.