Begemann M, Waszak SM, Robinson GW, et al. - Families with childhood medulloblastoma, one of the most common childhood malignant brain tumors, were examined to determine heritable predisposing germline mutations. A total of 1,044 medulloblastoma cases from international multicenter cohorts, comprising retrospective and prospective clinical studies and patient series was initially there. In six individuals with infant-onset medulloblastoma, heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene was discovered. In these cohorts, GPR161 mutations were exclusively related to the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases. Molecular tumor profiling showed a loss of heterozygosity at GPR161 in all impacted MBSHH tumors, atypical somatic copy number landscapes, and no further somatic driver events. Analysis of 226 MBSHH tumors exposed the somatic copy-neutral loss of heterozygosity of chromosome 1q as the trademark feature of GPR161 deficiency and in affected MBSHH tumors, as the principal mechanism for biallelic inactivation of GPR161. In conclusion, experts described a novel brain tumor predisposition syndrome that is induced by germline GPR161 mutations and identified by MBSHH in infants.