Neuroblastoma is a malignant tumor of the developing sympathetic nervous system, often presenting with widespread metastasis and poor survival rates. This study analyzed 240 high-risk neuroblastoma cases using whole exome, genome, and transcriptome sequencing to identify somatic mutations. The median exonic mutation frequency was 0.60 per megabase, with few recurrently mutated genes. Key mutated genes included ALK, PTPN11, ATRX, MYCN, and NRAS. Rare germline variants were enriched in ALK, CHEK2, PINK1, and BARD1. The low frequency of recurrent mutations challenges current therapeutic strategies targeting oncogenic drivers. The study also identified structural variations and rare germline variants associated with neuroblastoma. These findings suggest that rare germline variants and copy number alterations may play a significant role in neuroblastoma development. The study highlights the need for further research into the genetic factors contributing to neuroblastoma.Neuroblastoma is a malignant tumor of the developing sympathetic nervous system, often presenting with widespread metastasis and poor survival rates. This study analyzed 240 high-risk neuroblastoma cases using whole exome, genome, and transcriptome sequencing to identify somatic mutations. The median exonic mutation frequency was 0.60 per megabase, with few recurrently mutated genes. Key mutated genes included ALK, PTPN11, ATRX, MYCN, and NRAS. Rare germline variants were enriched in ALK, CHEK2, PINK1, and BARD1. The low frequency of recurrent mutations challenges current therapeutic strategies targeting oncogenic drivers. The study also identified structural variations and rare germline variants associated with neuroblastoma. These findings suggest that rare germline variants and copy number alterations may play a significant role in neuroblastoma development. The study highlights the need for further research into the genetic factors contributing to neuroblastoma.