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Abstract Background Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed. Methods We developed double batched sequencing where DNA samples are batch-sequenced twice — directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative (n = 100) and a validation (n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data. Results We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91–1.00 and 95% CI, 0.98–1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing. Conclusions Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.