Population-based whole-genome sequencing with constrained gene analysis identifies predisposing germline variants in children with central nervous system tumors

Background: The underlying cause of central nervous system (CNS) tumors in children is largely unknown. In this nationwide, prospective population-based study we investigate rare germline variants across known and putative CPS genes and genes exhibiting evolutionary intolerance of inactivating alterations in children with CNS tumors. Methods: One hundred and twenty-eight children with CNS tumors underwent whole-genome sequencing of germline DNA. Single nucleotide and structural variants in 315 cancer related genes and 2,986 highly evolutionarily constrained genes were assessed. A systematic pedigree analysis covering 3,543 close relatives was conducted. Results: Thirteen patients harbored rare pathogenic variants in nine known CPS genes. The likelihood of carrying pathogenic variants in CPS genes was higher for patients with medulloblastoma than children with other tumors (OR 5.9, CI 1.6-21.2). Metasynchronous CNS tumors were observed exclusively in children harboring pathogenic CPS gene variants (n=2, p=0.01). In general, known pCPS genes were shown to be significantly more constrained than both genes associated with risk of adult-onset malignancies (p=5e-4) and all other genes (p=5e-17). Forty-seven patients carried 66 loss-of-functions variants in 60 constrained genes, including eight variants in six known pCPS genes. A deletion in the extremely constrained EHMT1 gene, formerly somatically linked with sonic hedgehog medulloblastoma, was found in a patient with this tumor. Conclusions: {bsim}10% of pediatric CNS tumors can be attributed to rare variants in known CPS genes. Analysis of evolutionarily constrained genes may increase our understanding of pediatric cancer susceptibility.