Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

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Objective:To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiological and pathological abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.Methods:Targeted panel deep sequencing (>500X) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.Results:Brain-specific pathogenic somatic variants were found in six patients and heterozygous pathogenic germline variants were found in two. Somatic variants were identified in MTOR and germline variants were identified in DEPDC5 and NPRL3. Two patients with somatic MTOR variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent normal cortex.Conclusions:BOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.