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      Actionable, pathogenic incidental findings in 1,000 participants' exomes.

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          Abstract

          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 (∼3.4% for European descent and ∼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.

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          Author and article information

          Journal
          Am J Hum Genet
          American journal of human genetics
          Elsevier BV
          1537-6605
          0002-9297
          Oct 03 2013
          : 93
          : 4
          Affiliations
          [1 ] Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
          Article
          S0002-9297(13)00381-9
          10.1016/j.ajhg.2013.08.006
          3791261
          24055113
          655d2845-16c2-43b8-b607-d9bf1100eda3
          Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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