Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals

Paul Lacaze, Robert Sebra, Moeen Riaz, Jane Tiller, Jerico Revote, James Phung, Emily J. Parker, Suzanne G. Orchard, Jessica E. Lockery, Rory Wolfe, Maya Strahl, Ying C. Wang, Rong Chen, Daniel Sisco, Todd Arnold, Bryony A. Thompson, Daniel D. Buchanan, Finlay A. Macrae, Paul A. James, Walter P. AbhayaratnaTrevor J. Lockett, Peter Gibbs, Andrew M. Tonkin, Mark R. Nelson, Christopher M. Reid, Robyn L. Woods, Anne M. Murray, Ingrid Winship, John J. McNeil, Eric Schadt

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Purpose: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals. Methods: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards. Results: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders. Conclusion: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.

Original languageEnglish
Pages (from-to)1883-1886
Number of pages4
JournalGenetics in Medicine
Issue number11
Publication statusPublished - Nov 2020


  • genetic testing
  • healthy elderly
  • medical actionability
  • pathogenic variants
  • penetrance

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