Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes
Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes
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DOI：
10.1016/j.ajhg.2013.08.006
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发表时间：
2013-10-03
影响因子：
9.8
通讯作者：
Jarvik, Gail P.
中科院分区：
文献类型：
--
作者：
Dorschner, Michael O.;Amendola, Laura M.;Jarvik, Gail P.
基因组学与医学的结合激发了人们对从外显子组和基因组测序中获得的偶然发现（if）的兴趣。然而，目前还没有大规模的研究估计出每个人预期可采取行动的结果的数量；因此，我们从国家心脏、肺和血液研究所外显子组测序项目中随机选择了500名欧洲人和500名非洲人后裔参与者，对可操作的致病性单核苷酸变异进行了分类。这1000人被筛选114个基因的变异，这些基因是由一个专家小组选择的，因为它们与成人可能未诊断的医学上可操作的遗传条件有关。在1000名参与者中，在人类基因突变数据库（HGMD）中确定了239个独特变异的585个实例。本文回顾了支持该变异致病性的主要文献。在已确定的干扰素中，17个人中只有16种独特的常染色体显性变异被评估为致病性或可能致病性，一名参与者患有常染色体隐性疾病的两种致病性变异。此外，确定了一种致病变异和四种可能的致病变异，这些变异未被列为HGMD的致病原因。这些数据可以提供成人中高外显率可操作致病性或可能致病性变异的频率估计（类似于欧洲血统的3.4%和非洲血统的1.2%）。23名具有致病性或可能致病性变异的参与者是不成比例的欧洲血统（17人）和非洲血统（6人）。对这些变异进行分类的过程强调需要一个更全面和多样化的集中资源，为临床使用提供关于致病性的整理信息，以尽量减少基因组医学中的健康差异。
The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants' pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (similar to 3.4% for European descent and similar to 1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.