Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals
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...
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Published in | Genetics in medicine Vol. 22; no. 11; pp. 1883 - 1886 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.11.2020
Elsevier Limited |
Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authors’ contributions PL and RS conceived the study; I.W, E.S and J.J.M directed the research; J.J.M, R.L.W, A.M.M, A.M.T, M.R.N and C.M.R directed the ASPREE trial; J.R, M.R, M.S, Y.C.W, R.C, B.A.T, D.D.B, P.A.J contributed to genetic analysis and variant curation; P.G, A.M.T, J.E.L, R.W and F.A.M contributed to the design and conduct of the ASPREE trial; R.L.W, J.P, E.J.P, S.G.O, W.P.A, T.J.L, R.L.W, and J.J.M contributed to collection of biospecimens; R.S, R.C, D.S, T.A, M.S, Y.C.W and E.S contributed to panel design, DNA sequencing and variant calling; D.S, M.R and J.R contributed to the preparation of genetic data; D.D.B, F.A.M, P.A.J and I.W contributed to clinical interpretation of genetic variants; P.L wrote the manuscript, with editing from J.T, R.S, I.W and J.J.M. All authors reviewed the manuscript. Joint senior authors Joint first authors |
ISSN: | 1098-3600 1530-0366 |
DOI: | 10.1038/s41436-020-0881-7 |