Dataset Information

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.

SUBMITTER: Lacaze P

PROVIDER: S-EPMC7606791 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Lacaze Paul P Sebra Robert R Riaz Moeen M Tiller Jane J Revote Jerico J Phung James J Parker Emily J EJ Orchard Suzanne G SG Lockery Jessica E JE Wolfe Rory R Strahl Maya M Wang Ying C YC Chen Rong R Sisco Daniel D Arnold Todd T Thompson Bryony A BA Buchanan Daniel D DD Macrae Finlay A FA James Paul A PA Abhayaratna Walter P WP Lockett Trevor J TJ Gibbs Peter P Tonkin Andrew M AM Nelson Mark R MR Reid Christopher M CM Woods Robyn L RL Murray Anne M AM Winship Ingrid I McNeil John J JJ Schadt Eric E

Genetics in medicine : official journal of the American College of Medical Genetics 20200701 11

<h4>Purpose</h4>To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.<h4>Methods</h4>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 di ...[more]

PMID: 32606442

Similar Datasets

Project description:The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

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