Pathogenic germline variations and cancer risks in pediatric patients referred for genetic testing

Next-generation sequencing technologies have been widely applied in diagnosing genetic disorders in pediatric patients. However, the cancer predisposition and tumor characteristics in individuals who have germline pathogenic variants remain unclear. We analyzed exome sequencing data from 75,602 pediatric patients referred for genetic testing between January 2016 and January 2025, tracking cancer as a secondary finding. The most common reasons for genetic testing were symptoms related to the nervous system, metabolic disorders and immune dysfunction. Among 110,692 variants of 139 tumor susceptibility genes, we identified 501 (456 single-nucleotide variants, 45 copy number variations, 0.45%) pathogenic or likely pathogenic (P/LP) and 3,848 (3,650 single-nucleotide variants, 198 copy number variations, 3.5%) variants of uncertain significance leaning toward likely pathogenic variants. Of 411 patients with tumors (203 with preexisting tumors and 208 with new tumors diagnosed during follow-up), 134 (32.6%) harbored causative germline P/LP variants in genes such as NF1 (13.1%), TSC2 (5.8%), RB1 (4.6%) and WT1 (3.2%). Critically, prospective follow-up of 64,187 patients without initial tumors revealed a significantly higher incidence of malignant tumors in those carrying P/LP variants (3.23 per 1,000 person-years) compared with those with variants of uncertain significance leaning toward likely pathogenic or other variants (0.236 and 0.272 per 1,000 person-years, respectively). These findings underscore the importance of proactive genetic counseling and surveillance for pediatric patients with pathogenic germline variants.