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

Paul Lacaze¹, Robert Sebra^{2

3}, Moeen Riaz⁴, Jane Tiller⁴, Jerico Revote⁴, James Phung⁴, Emily J Parker⁴, Suzanne G Orchard⁴, Jessica E Lockery⁴, Rory Wolfe⁴, Maya Strahl², Ying C Wang², Rong Chen^{2

3}, Daniel Sisco³, Todd Arnold³, Bryony A Thompson⁵, Daniel D Buchanan^{5

6}, Finlay A Macrae⁵, Paul A James⁵, Walter P Abhayaratna⁷, Trevor J Lockett⁸, Peter Gibbs⁹, Andrew M Tonkin⁴, Mark R Nelson^{4

10}, Christopher M Reid^{4

11}, Robyn L Woods⁴, Anne M Murray¹², Ingrid Winship⁵, John J McNeil⁴, Eric Schadt^{2

3}

Affiliations

¹ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. paul.lacaze@monash.edu.
² Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Sema4, Stamford, CT, USA.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
⁵ Department of Genomic Medicine; Family Cancer Clinic, Department of Medicine, Department of Pathology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.
⁷ College of Health and Medicine, The Australian National University, Canberra, Australia.
⁸ CSIRO Health and Biosecurity, North Ryde, NSW, Australia.
⁹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
¹⁰ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
¹¹ School of Public Health, Curtin University, Perth, WA, Australia.
¹² Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Hennepin Healthcare, University of Minnesota, Minneapolis, MN, USA.

PMID: 32606442
PMCID: PMC7606791
DOI: 10.1038/s41436-020-0881-7

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

Paul Lacaze et al. Genet Med. 2020 Nov.

. 2020 Nov;22(11):1883-1886.

doi: 10.1038/s41436-020-0881-7. Epub 2020 Jul 1.

Authors

Affiliations

¹ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. paul.lacaze@monash.edu.
² Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Sema4, Stamford, CT, USA.
⁴ Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
⁵ Department of Genomic Medicine; Family Cancer Clinic, Department of Medicine, Department of Pathology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
⁶ Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.
⁷ College of Health and Medicine, The Australian National University, Canberra, Australia.
⁸ CSIRO Health and Biosecurity, North Ryde, NSW, Australia.
⁹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
¹⁰ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
¹¹ School of Public Health, Curtin University, Perth, WA, Australia.
¹² Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Hennepin Healthcare, University of Minnesota, Minneapolis, MN, USA.

PMID: 32606442
PMCID: PMC7606791
DOI: 10.1038/s41436-020-0881-7

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.

Keywords: genetic testing; healthy elderly; medical actionability; pathogenic variants; penetrance.

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Conflict of interest statement

Conflict of interest: The authors declare no conflict of interest.

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

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

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