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.
Genet Med. 2020 Nov;22(11):1883-1886. doi: 10.1038/s41436-020-0881-7. Epub 2020 Jul 1.
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.
在健康老年人群体中测量医学上可干预的致病性变异（PV）的流行率。
我们使用靶向测序，在参与 ASPirin in Reducing Events in the Elderly（ASPREE）试验的 13131 名 70 岁或以上（平均年龄 75 岁）的个体中，检测与常染色体显性遗传的医学上可干预疾病相关的 55 个基因中的致病性或可能致病性变异。参与者无先前的心血管疾病、身体残疾或痴呆症诊断或当前症状，也无危及生命的癌症的当前诊断。变异的管理遵循美国医学遗传学与基因组学学院/分子病理学协会（ACMG/AMP）标准。
每 75 名健康老年人中就有 1 人携带 PV（1.3%）。这低于基于人群的研究报告的比率，这些研究的比率范围为 1.8%至 3.4%。我们检测到 20 名 Lynch 综合征（MSH6/MLH1/MSH2/PMS2）的 PV 携带者和 13 名家族性高胆固醇血症（LDLR/APOB/PCSK9）的 PV 携带者。在 7056 名女性参与者中，我们检测到 15 名 BRCA1/BRCA2 PV 携带者（每 470 名女性中有 1 名）。我们在与遗传性心脏疾病相关的低外显率基因中检测到 86 名 PV 携带者。
医学上可干预的 PV 存在于健康的老年人群中。我们的发现提出了关于低外显率基因的可操作性问题，特别是当在没有疾病症状和/或家族史的情况下检测到 PV 时。
