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

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Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-07-01 , DOI: 10.1038/s41436-020-0881-7
Paul Lacaze ₁ , Robert Sebra _{2,

3} , Moeen Riaz ₁ , Jane Tiller ₁ , Jerico Revote ₁ , James Phung ₁ , Emily J Parker ₁ , Suzanne G Orchard ₁ , Jessica E Lockery ₁ , Rory Wolfe ₁ , Maya Strahl ₂ , Ying C Wang ₂ , Rong Chen _{2,

3} , Daniel Sisco ₃ , Todd Arnold ₃ , Bryony A Thompson ₄ , Daniel D Buchanan _{4,

5} , Finlay A Macrae ₄ , Paul A James ₄ , Walter P Abhayaratna ₆ , Trevor J Lockett ₇ , Peter Gibbs ₈ , Andrew M Tonkin ₁ , Mark R Nelson _{1,

9} , Christopher M Reid _{1,

10} , Robyn L Woods ₁ , Anne M Murray ₁₁ , Ingrid Winship ₄ , John J McNeil ₁ , Eric Schadt _{2,

3}

Affiliation

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
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.
Sema4, Stamford, CT, USA.
Department of Genomic Medicine; Family Cancer Clinic, Department of Medicine, Department of Pathology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia.
College of Health and Medicine, The Australian National University, Canberra, Australia.
CSIRO Health and Biosecurity, North Ryde, NSW, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
School of Public Health, Curtin University, Perth, WA, Australia.
Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Hennepin Healthcare, University of Minnesota, Minneapolis, MN, USA.

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.

中文翻译：

在 13,131 名健康老年人群中的医学上可行的致病变异。

目的

测量健康老年人群中医学上可行的致病变异 (PV) 的流行率。

方法

我们使用靶向测序在 13,131 名年龄在 70 岁或以上（平均年龄 75 岁）的人群中检测了与常染色体显性遗传疾病相关的 55 个基因中的致病性或可能致病性变异（ASPREE）。）审判。参与者之前没有心血管疾病、身体残疾或痴呆的诊断或当前症状，目前也没有诊断出威胁生命的癌症。变体管理遵循美国医学遗传学和基因组学/分子病理学协会 (ACMG/AMP) 标准。

结果

75 名 (1.3%) 健康老年人中就有一名携带 PV。这低于基于人群的研究报告的比率，该比率从 1.8% 到 3.4% 不等。我们检测到 20 名患有 Lynch 综合征的 PV 携带者 ( MSH6/MLH1/MSH2/PMS2 ) 和 13 名患有家族性高胆固醇血症 ( LDLR/APOB/PCSK9 )。在 7056 名女性参与者中，我们检测到 15名BRCA1/BRCA2 PV 携带者（470 名女性中有 1 名）。我们在与遗传性心脏病相关的低外显率基因中检测到 86 个 PV 携带者。