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

Abstract

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.

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Data and code availability

Data and code can be provided upon reasonable request from the corresponding author.

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Acknowledgements

Supported by a Flagship cluster grant (including the Commonwealth Scientific and Industrial Research Organisation, Monash University, Menzies Research Institute, Australian National University, University of Melbourne), grants U01AG029824 from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants 334047 and 1127060 from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency. We thank the trial staff in Australia and the United States, the participants who volunteered for this trial, and the general practitioners and staff of the medical clinics who cared for the participants.

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Correspondence to Paul Lacaze PhD.

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The authors declare no conflicts of interest.

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This work was approved by the Alfred Hospital Human Research Ethics Committee (project 390/15) in accordance with the National Statement on Ethical Conduct in Human Research (2007).

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Joint first authors: Paul Lacaze, Robert Sebra

Joint senior authors: Ingrid Winship, John J McNeil, Eric Schadt

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Lacaze, P., Sebra, R., Riaz, M. et al. Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals. Genet Med (2020). https://doi.org/10.1038/s41436-020-0881-7

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Keywords

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