ABSTRACT The role of germline genetic variation and viral infection in development and progression has been studied extensively in adult tumors and autoimmune disease. Less attention has been paid to the interaction of these factors with birth defects and pediatric malignancies, particularly acute myeloid leukemia (AML), which in the youngest patients is driven almost exclusively by structural variants (SVs) with poorly understood etiology. The prevalence of gene fusion transcripts associated with leukemia at live birth is 10x to 100x greater than the incidence of childhood leukemia, which suggests other risk factors must interact with SVs. One possible candidate for interaction is the timing of viral infection, either in parents or children. Clinical trials of gene therapy with viral vectors failed in part due to viral integrations activating oncogenes such as MECOM. Recent work has shown a direct mechanism for derivative chromosome formation at the most common breakpoints in leukemia, and human herpesviruses, including CMV, are one of the single greatest risk factors for chromosomal birth defects. Elsewhere, we and others have documented germline and somatic copy number and short sequence variants affecting e26 transformation specific (ETS) factors, which participate in high-risk gene fusions seen in both solid and liquid tumors. These factors and their binding sites determine developmental fates across tissues, yet their motifs are short tandem repeats -- the single most variable class of features in the human genome. Small changes in dosage, as created by haploinsufficiency or variation in ramp sequences, may be sufficient to predispose individuals to disease. The primary obstacle to studying either of these mechanisms has long been the small sample sizes and biased coverage of cohorts assembled for rare and childhood diseases. The vast quantity of whole-genome, whole-transcriptome, and long-read sequencing data provided by the Gabriella Miller Kids First! (GMKF) Consortium and the INCLUDE cohorts negate this obstacle. When combined with the thousands of pediatric clinical trial participants in Project: Every Child, and the forthcoming X01 Long Read Pilot Project for omics-cold pediatric leukemia patients, we posit that both the computational infrastructure and the sample sizes required for progress are now in place. We propose to characterize germline regulatory, splicing, and structural variants as catalysts of risk for leukemia and related preleukemic conditions, noting that triplication of the ETS factor ERG is an inherent feature of Down syndrome-driven disease (a 500x multiplier for risk over the general population). With colleagues, we have identified non-coding variants with strong effects in Down syndrome. This suggests that the combination of sample size, cohort diversity, and representation of the most common structural variants in human disease within the GMKF! Consortium presents an ideal opportunity to address this urgent need a...