A major familial neuroblastoma predisposition gene, ALK, was identified through genetic analysis of neuroblastoma pedigrees. Germline mutations in the ALK gene, specifically in the tyrosine kinase domain, were found to explain the majority of hereditary neuroblastomas. These mutations, including G1128A, R1192P, and R1275Q, were associated with disease in multiple families. Additionally, somatic mutations in the ALK domain were detected in high-risk neuroblastoma samples, with nine out of ten mutations located in critical regions of the kinase domain and predicted to be oncogenic drivers. These mutations led to constitutive phosphorylation and growth inhibition in cell lines harboring mutant or amplified ALK. The study also showed that ALK copy number gains and amplifications were highly associated with aggressive clinical phenotypes and poor prognosis. ALK mutations were found in families with high or moderate confidence of heritability, while families with low confidence did not show ALK alterations. The findings suggest that heritable ALK mutations are the major cause of familial neuroblastoma, and that germline or acquired activation of ALK is a tractable therapeutic target for this lethal pediatric malignancy. The study highlights the importance of genetic screening for ALK mutations in families with a history of neuroblastoma, as it provides a potential non-invasive method for early detection and intervention. The results also emphasize the need for further research to characterize the full spectrum of ALK mutations and their frequency across different neuroblastoma subtypes.A major familial neuroblastoma predisposition gene, ALK, was identified through genetic analysis of neuroblastoma pedigrees. Germline mutations in the ALK gene, specifically in the tyrosine kinase domain, were found to explain the majority of hereditary neuroblastomas. These mutations, including G1128A, R1192P, and R1275Q, were associated with disease in multiple families. Additionally, somatic mutations in the ALK domain were detected in high-risk neuroblastoma samples, with nine out of ten mutations located in critical regions of the kinase domain and predicted to be oncogenic drivers. These mutations led to constitutive phosphorylation and growth inhibition in cell lines harboring mutant or amplified ALK. The study also showed that ALK copy number gains and amplifications were highly associated with aggressive clinical phenotypes and poor prognosis. ALK mutations were found in families with high or moderate confidence of heritability, while families with low confidence did not show ALK alterations. The findings suggest that heritable ALK mutations are the major cause of familial neuroblastoma, and that germline or acquired activation of ALK is a tractable therapeutic target for this lethal pediatric malignancy. The study highlights the importance of genetic screening for ALK mutations in families with a history of neuroblastoma, as it provides a potential non-invasive method for early detection and intervention. The results also emphasize the need for further research to characterize the full spectrum of ALK mutations and their frequency across different neuroblastoma subtypes.