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Prioritizing the detection of rare pathogenic variants in population screening

Population genomic screening to detect carriers of rare monogenic variants for medically actionable conditions is supported by substantial evidence of clinical utility and cost effectiveness. Much less evidence supports screening by polygenic risk scores, which do not detect rare variants. Using only polygenic scores in population screening initiatives, while ignoring the detection of higher-risk rare monogenic variants, is ill-advised.

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The authors thank J. Tiller for her input into this article. P.L. is supported by a National Heart Foundation Future Leader Fellowship (102604) and grants from the Australian Government Department of Health, Medical Research Future Fund, Genomics Health Futures Mission (APP2009024) and National Institutes of Health (1127060). R.M. is funded by the Yorkshire Cancer Research and Eve Appeal into Population testing and has been supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing. R.C.G. is funded by NIH grants: TR003201, HG008685, HL143295, OD026553 and by the Franca Sozzani Fund for Preventive Genomics.

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The authors contributed equally to all aspects of the manuscript.

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Correspondence to Paul Lacaze.

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R.M. declares advisory board membership from Astrazeneca/MSD/EGL/GSK. R.C.G. has received compensation for advising Allelica, Fabric, GenomeWeb, Genomic Life and Verily; and is a co-founder of Genome Medical and Nurture Genomics. P.L. declares no competing interests.

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Lacaze, P., Manchanda, R. & Green, R.C. Prioritizing the detection of rare pathogenic variants in population screening. Nat Rev Genet 24, 205–206 (2023).

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