Mateos, Marion K.Ajuyah, PamelaFuentes-Bolanos, NoemiEl-Kamand, SamBarahona, PauletteAlteköester, Ann-KristinMayoh, ChelseaHolliday, HollyLiu, JieCui, LujingPfaff, ElkeMackay, AlanResnick, Adam CPinese, MarkLau, Loretta M. S.Khuong-Quang, Dong-AnhDias, KimberlyGoudie, CatherineSalkeld, AlisonRokita, Jo LynneJones, DavidJuretic, NikoletaHayden, ElishaPfister, Stefan M.Kramm, Christof M.Blattner-Johnson, MirjamJabado, NadaTsoli, MariaVittorio, OrazioMueller, SabineGuo, YiranTucker, KathyWaszak, Sebastian M.Perreault, SébastienJones, ChrisWong, MarieCowley, Mark J.Ziegler, David S.2025-05-272025-05-272025-05-242025-03-1210.1093/neuonc/noaf061https://infoscience.epfl.ch/handle/20.500.14299/250675Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG. We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n = 153), with germline whole genome or whole exome sequencing. We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with the absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = .023). P/LP germline variants were recurrent in homologous recombination (n = 9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n = 4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed a near-complete radiological response to PARP and immune checkpoint inhibition. Our study determined the prevalence of pathogenic germline variants in pediatric DMG and suggests a role in tumorigenesis for a subset of patients.entext::journal::journal article::research article