Genomic Landscape and Clinical Predictors of Germline Variants in Pediatric CNS Tumors in a Highly Consanguineous Population

Background Due to high consanguinity, pediatric central nervous system (CNS) tumors in Saudi Arabia are increasingly recognized as manifestations of cancer predisposition syndromes (CPS). This study evaluates the diagnostic yield and clinical correlations of comprehensive germline profiling in this population. Methods A 10-year retrospective review (2015–2025) included a selected cohort of 104 pediatric CNS tumor patients who met American College of Medical Genetics and Genomics (ACMG) criteria at King Fahad Medical City. Patients underwent Whole Exome Sequencing (WES) or targeted next-generation sequencing (NGS) panels to evaluate mutational spectra, clinical predictors, and survival outcomes. Results With a median follow-up of 3.1 years, the cohort (median age 4.5 years) exhibited 72.1% consanguinity and 46.2% positive family history. Cutaneous stigmata strongly predicted genetic positivity (p < 0.001). A germline variant was identified in 54 of the 104 patients. The definitive diagnostic yield of pathogenic/likely pathogenic (P/LP) variants was 39.4% (n = 41), substantially exceeding typical Western benchmarks, with an additional 12.5% (n = 13) harboring variants of uncertain significance (VUS). Among the 41 patients with confirmed P/LP variants, the most frequent diagnoses were Constitutional Mismatch Repair Deficiency (CMMRD) (24.4%), Neurofibromatosis type 1 (NF1) (22.0%), and Li-Fraumeni Syndrome (14.6%). Furthermore, secondary neoplasms (8.7%) developed significantly faster in genetically positive cases (median 3.32 vs. 6.81 years). Conclusions A clinically selected cohort of pediatric CNS tumors in Saudi Arabia harbors a distinct genetic profile driven by consanguinity, featuring an enrichment of highly penetrant autosomal recessive syndromes. Broad molecular profiling is essential for optimizing clinical care and facilitating preventative familial screening within the region.