To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.
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.
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.
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.
Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–255.
Directors ABO. The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21:1467–1468.
Linderman MD, Nielsen DE, Green RC. Personal genome sequencing in ostensibly healthy individuals and the PeopleSeq Consortium. J Pers Med. 2016;6:14.
Schwartz MLB, McCormick CZ, Lazzeri AL, Lindbuchler DM, Hallquist MLG, Manickam K, et al. A model for genome-first care: returning secondary genomic findings to participants and their healthcare providers in a large research cohort. Am J Hum Genet. 2018;103:328–337.
Carey DJ, Fetterolf SN, Davis FD, Faucett WA, Kirchner HL, Mirshahi U, et al. The Geisinger MyCode community health initiative: an electronic health record-linked biobank for precision medicine research. Genet Med. 2016;18:906–913.
Dewey FE, Murray MF, Overton JD, Habegger L, Leader JB, Fetterolf SN, et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 2016;354:aaf6814.
Haer-Wigman L, van der Schoot V, Feenstra I, Vulto-van Silfhout AT, Gilissen C, Brunner HG, et al. 1 in 38 individuals at risk of a dominant medically actionable disease. Eur J Hum Genet. 2019;27:325–330.
McNeil JJ, Woods RL, Nelson MR, Reid CM, Kirpach B, Wolfe R, et al. Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379:1499–1508.
Group AI. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials. 2013;36:555–564.
Lockery JE, Collyer TA, Abhayaratna WP, Fitzgerald SM, McNeil JJ, Nelson MR, et al. Recruiting general practice patients for large clinical trials: lessons from the Aspirin in Reducing Events in the Elderly (ASPREE) study. Med J Aust. 2019;210:168–173.
McNeil JJ, Woods RL, Nelson MR, Murray AM, Reid CM, Kirpach B, et al. Baseline characteristics of participants in the ASPREE (ASPirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. 2017;72:1586–1593.
Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, et al. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(Database issue):D980–D985.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424.
Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317:2402–2416.
Moller P, Seppala TT, Bernstein I, Holinski-Feder E, Sala P, Gareth Evans D, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut. 2018;67:1306–1316.
Lacaze P, Ryan J, Woods R, Winship I, McNeil J. Pathogenic variants in the healthy elderly: unique ethical and practical challenges. J Med Ethics. 2017;43:714–722.
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.
The authors declare no conflicts of interest.
Ethics committee approval
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
- pathogenic variants
- medical actionability
- genetic testing
- healthy elderly