Pediatric High-Grade Gliomas and Cancer Predisposition Syndromes: A Retrospective Study

: The relationship between pediatric and adolescent/young adult (AYA) patients with high-grade gliomas (pHGGs) and cancer predisposition syndromes (CPSs) remains insufficiently explored, despite the increasing use of massive parallel sequencing in the diagnostic setting. We retrospectively analyzed sequencing data from 95 pediatric patients diagnosed with high-grade gliomas to investigate the presence of germline variants associated with cancer risk. The presence of somatic variants was also evaluated in 15 cases. In silico and in vitro studies were performed to reclassify one variant of uncertain significance (VUS). We identified 80 variants across the 95 patients, including 17 pathogenic (P), 2 likely pathogenic (LP), 60 VUSs, and 1 likely benign (LB), after reclassification. Notably, 23.7% of the P/LP variants were found in genes associated with CPSs. While the distribution of these variants did not show significant differences across tumor subtypes, the highest proportion of P/LP variants was observed in diffuse midline gliomas. Functional studies led to the reclassification of one LZTR1 variant from VUS to LP. The collected data revealed that 18.9% of patients had P/LP variants; notably, among the 11.6% of patients carrying P/LP variants, there were variants in genes known to be associated with the development of CNS tumors in pediatric and AYA patients, a rate higher than the 10% incidence typically reported in the literature for pediatric central nervous system tumors. This finding emphasizes the value of our comprehensive analysis for germline variants in HGG, suggesting a greater prevalence of CPS in these patients than previously reported.