Rego Shannon, Dagan-Rosenfeld Orit, Zhou Wenyu, Sailani M Reza, Limcaoco Patricia, Colbert Elizabeth, Avina Monika, Wheeler Jessica, Craig Colleen, Salins Denis, Röst Hannes L, Dunn Jessilyn, McLaughlin Tracey, Steinmetz Lars M, Bernstein Jonathan A, Snyder Michael P
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Cold Spring Harb Mol Case Stud. 2018 Dec 17;4(6). doi: 10.1101/mcs.a003178. Print 2018 Dec.
Exome sequencing is increasingly utilized in both clinical and nonclinical settings, but little is known about its utility in healthy individuals. Most previous studies on this topic have examined a small subset of genes known to be implicated in human disease and/or have used automated pipelines to assess pathogenicity of known variants. To determine the frequency of both medically actionable and nonactionable but medically relevant exome findings in the general population we assessed the exomes of 70 participants who have been extensively characterized over the past several years as part of a longitudinal integrated multiomics profiling study. We analyzed exomes by identifying rare likely pathogenic and pathogenic variants in genes associated with Mendelian disease in the Online Mendelian Inheritance in Man (OMIM) database. We then used American College of Medical Genetics (ACMG) guidelines for the classification of rare sequence variants. Additionally, we assessed pharmacogenetic variants. Twelve out of 70 (17%) participants had medically actionable findings in Mendelian disease genes. Five had phenotypes or family histories associated with their genetic variants. The frequency of actionable variants is higher than that reported in most previous studies and suggests added benefit from utilizing expanded gene lists and manual curation to assess actionable findings. A total of 63 participants (90%) had additional nonactionable findings, including 60 who were found to be carriers for recessive diseases and 21 who have increased Alzheimer's disease risk because of heterozygous or homozygous e4 alleles (18 participants had both). Our results suggest that exome sequencing may have considerably more utility for health management in the general population than previously thought.
外显子组测序在临床和非临床环境中的应用越来越广泛，但人们对其在健康个体中的效用知之甚少。此前关于这一主题的大多数研究都只考察了一小部分已知与人类疾病相关的基因，和/或使用自动化流程来评估已知变异的致病性。为了确定普通人群中具有医学可操作性以及虽无医学可操作性但与医学相关的外显子组发现的频率，我们评估了70名参与者的外显子组，这些参与者在过去几年中作为一项纵向综合多组学分析研究的一部分，已得到广泛的特征描述。我们通过在《人类孟德尔遗传》（OMIM）数据库中识别与孟德尔疾病相关基因中的罕见可能致病和致病变异来分析外显子组。然后，我们使用美国医学遗传学学会（ACMG）的指南对罕见序列变异进行分类。此外，我们还评估了药物遗传学变异。70名参与者中有12名（17%）在孟德尔疾病基因中具有医学可操作性的发现。其中5名有与其基因变异相关的表型或家族史。可操作变异的频率高于此前大多数研究报告的频率，这表明利用扩展的基因列表和人工筛选来评估可操作发现会带来更多益处。共有63名参与者（90%）有其他不可操作的发现，其中60名被发现是隐性疾病的携带者，21名由于杂合或纯合的ε4等位基因而增加了患阿尔茨海默病的风险（18名参与者两者都有）。我们的结果表明，外显子组测序在普通人群的健康管理中的效用可能比之前认为的要大得多。
