In conclusion, although functional studies in a mouse model are needed to characterize the influence of both the novel P101L and previously described T323M PNKP alterations on brain tumor initiation, we speculate that mutant PNKP-driven impaired DNA damage response and higher spontaneous mutation rates contributed to the generation of pediatric glioma associated driver mutations such as TP53 and ATRX in the clinical case described. Here, PNKP is linked to glioma.