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Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights



Genetic testing for pediatric cancer predisposition syndromes (CPS) could augment newborn screening programs, but with uncertain benefits and costs.


We developed a simulation model to evaluate universal screening for a CPS panel. Cohorts of US newborns were simulated under universal screening versus usual care. Using data from clinical studies, ClinVar, and gnomAD, the presence of pathogenic/likely pathogenic (P/LP) variants in RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, and PHOX2B were assigned at birth. Newborns with identified variants underwent guideline surveillance. Survival benefit was modeled via reductions in advanced disease, cancer deaths, and treatment-related late mortality, assuming 100% adherence.


Among 3.7 million newborns, under usual care, 1,803 developed a CPS malignancy before age 20. With universal screening, 13.3% were identified at birth as at-risk due to P/LP variant detection and underwent surveillance, resulting in a 53.5% decrease in cancer deaths in P/LP heterozygotes and a 7.8% decrease among the entire cohort before age 20. Given a test cost of $55, universal screening cost $244,860 per life-year gained; with a $20 test, the cost fell to $99,430 per life-year gained.


Population-based genetic testing of newborns may reduce mortality associated with pediatric cancers and could be cost-effective as sequencing costs decline.

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Fig. 1: Modeled clinical outcomes for targeted next-generation sequencing (t-NGS) vs. usual care.

Data availability

Additional details about the Precision Medicine Policy and Treatment (PreEMPT) model, data used as model input parameters, and output data from the model are available by request from the corresponding author. A list of variants included in the modeling study is also provided in Supplemental Table 2.


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We thank Matt Lebo, Sami Amr, Lorena Lazo de la Vega, Lisa Marie Mahanta, and Natascia Anastasio for curating the variant list.

Author information




Conceptualization: J.M.Y., N.K.S., K.D.C., P.M.M., C.L.B.Z., R.C.G., C.Y.L., H.L.R., M.S.W., L.D., A.C.W. Data curation: J.M.Y., N.K.S., A.C., K.D.C., P.M.M., M.G., C.L.B.Z., L.D., A.C.W. Formal analysis: J.M.Y., N.K.S., K.D.C., P.M.M., G.O., M.G., N.R., L.D., A.C.W. Funding acquisition: J.M.Y., N.K.S., R.C.G., A.C.W. Investigation: J.M.Y., N.K.S., A.C., K.D.C., P.M.M., G.O., N.R., C.L.B.Z., R.C.G., H.L.R., M.S.W., L.D., A.C.W. Methodology: J.M.Y., N.K.S., K.D.C., P.M.M., M.G., A.C.W. Visualization: J.Y., G.O., N.R. Writing—original draft: J.M.Y., N.K.S., K.D.C., P.M.M., G.O., C.L.B.Z., R.C.G., H.L.R., M.S.W., L.D., A.C.W. Writing—review & editing: J.M.Y., N.K.S., A.C., K.D.C., M.G., P.M.M., G.O., N.R., C.L.B.Z., R.C.G., C.Y.L., H.L.R., M.S.W., L.D., A.C.W.

Corresponding author

Correspondence to Jennifer M. Yeh.

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Competing interests

This project was funded by the National Institutes of Health (NIH) (5R01HD090019–04, principal investigator [PI] A.C.W.), which had no role in the design of the study, collection and analysis of data and decision to publish. K.D.C. was supported by NIH grant K01-HG009173. R.C.G. is co-founder of Genome Medical, Inc. and has received compensation for advising AIA, Grail, Humanity, Kneed Media, Plumcare, UnitedHealth, Verily, VibrentHealth, and Wamberg. H.L.R. serves on the Scientific Advisory Board for Genome Medical, Inc. The other authors declare no competing interests.

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Yeh, J.M., Stout, N.K., Chaudhry, A. et al. Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights. Genet Med (2021).

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