• Hui-Qi Qu, Joseph T Glessner, Jingchun Qu, Yichuan Liu, Deborah Watson, Xiao Chang, Amir Hossein Saeidian, Haijun Qiu, Frank D Mentch, John J Connolly, and Hakon Hakonarson.
• Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA.
• Transl Res. 2024 Apr 1; 266: 495649-56.

BackgroundPatients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions.MethodsThis study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program.Results8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 patients including 17 males. Large recurrent P/LP duplications >5MB were detected in 33 patients.ConclusionsThis study revealed that P/LP CNVs were common in a large cohort of BD patients with high rate of pediatric cancers. We present a comprehensive spectrum of P/LP CNVs in patients with BDs and various cancers. Notably, deletions involving E2F target genes and genes implicated in mitotic spindle assembly and G2/M checkpoint were identified, potentially disrupting cell-cycle progression and providing mechanistic insights into the concurrent occurrence of BDs and cancers.Copyright © 2023. Published by Elsevier Inc.

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