Abstract
PURPOSE: Although congenital anomalies are among the strongest risk factors for developing pediatric cancer, the genetic underpinnings remain unclear. Therefore, we evaluated germline susceptibility in children with congenital anomalies and cancer. METHODS: Through the Genetic Overlap Between Anomalies and Cancer in Kids Study, we recruited 47 participants with anomalies and cancer, along with their biological families. Genome sequencing was performed, focusing on single-nucleotide variants, indels, and structural variants. Pathogenic or likely pathogenic variants were identified by the American College of Medical Genetics and Genomics classification. RESULTS: We identified pathogenic or likely pathogenic variants in 23.4% (11 of 47) of participants. These variants encompassed (1) 4 genes associated with both anomalies and cancer (WT1, USP9X, PTPN1, and LZTR1), (2) 2 established cancer predisposition genes (TP53 in 2 participants and PAX5), and (3) 4 genes that are associated with anomalies (MMUT, FBN1, COL3A1, and KAT6B). We further investigated the role of KAT6B on neuroblastoma in a gene-based analysis from 409 neuroblastoma cases and 952 controls. This analysis demonstrated a significant enrichment of rare, predicted deleterious variants (P = .017), with odds ratios ranging from 2 to 4 based on the conditions we applied. CONCLUSION: This study demonstrates a molecular diagnostic yield of 23.4% in participants with both anomalies and cancer. Additionally, the findings further implicate the role of KAT6B as a novel neuroblastoma predisposition gene.