viernes, 4 de octubre de 2013

AJHG - Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

AJHG - Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

Copyright © 2013 The American Society of Human Genetics All rights reserved.
The American Journal of Human Genetics, Volume 93, Issue 4, 631-640, 19 September 2013
doi:10.1016/j.ajhg.2013.08.006
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Article

Actionable, Pathogenic Incidental Findings in 1,000 Participants’ Exomes

Michael O. Dorschner145Laura M. Amendola2Emily H. Turner15Peggy D. Robertson1Brian H. Shirts5Carlos J. Gallego2Robin L. Bennett2Kelly L. Jones2Mari J. Tokita2James T. Bennett23Jerry H. Kim8Elisabeth A. Rosenthal2Daniel S. Kim1National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing ProjectHolly K. Tabor36Michael J. Bamshad13Arno G. Motulsky12C. Ronald Scott23Colin C. Pritchard5Tom Walsh2Wylie Burke26Wendy H. Raskind24Peter Byers27Fuki M. Hisama2Deborah A. Nickerson1 and Gail P. Jarvik12Go To Corresponding Author 
1 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
2 Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA
3 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
4 Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA
5 Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA
6 Department of Bioethics and Humanities, University of Washington, Seattle, WA 98195, USA
7 Department of Pathology, University of Washington, Seattle, WA 98195, USA
8 Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98195, USA
Corresponding author


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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