Work

Germline Variants in Centromere Binding Protein 126 Predispose to Glioblastoma

Year: 2026

Type: preprint

Abstract: Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. While only 5% of GBM cases arise in a familial context, the genetic basis of familial GBM remains unresolved in most affected clusters, suggesting that important susceptibility variants may reside outside recognized cancer-predisposition genes. Proband-based genomic studies of such families provide a rational path to discover rare inherited variants with large biological effects, prioritize candidate genes for functional validation, and define early mechanisms of gliomagenesis that may not be apparent from studies of sporadic tumors alone. Methods: In this study, we investigated a family with GBM clustering spanning two generations. To investigate the possibility of shared germline susceptibility, we enrolled the proband and their two confirmed affected relatives in our study and performed whole-genome sequencing on available whole blood and tumor samples. Rare coding variants shared among the three study participants were identified and the genes harboring these variants were functionally interrogated with pooled loss-of-function CRISPR screens in human neural progenitor cells (NPCs) in vitro and in heterotopic xenograft models. Results: Rare coding variants were identified in 139 candidate genes, and functional genetic screens of human NPCs in heterotopic xenograft models revealed Centrosomal Protein of 126 kDa (CEP126), as the top hit. Genetic disruption of CEP126 conferred a survival and tumorigenic advantage in neural progenitor cells. Conclusion: Together, our results establish a functional framework for interrogating rare cancer germline variants and highlights CEP126 as a biologically tractable GBM predisposition gene for future mechanistic and genetic validation.

Source: medRxiv

DOI: 10.64898/2026.07.20.26358470