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High-frequency actionable pathogenic exome variants in an average-risk cohort

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318774/
https://www.ncbi.nlm.nih.gov/pubmed/30487145
http://dx.doi.org/10.1101/mcs.a003178
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author 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.
author_facet 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.
author_sort Rego, Shannon
collection PubMed
description 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 APOE 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.
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spelling pubmed-63187742019-01-13 High-frequency actionable pathogenic exome variants in an average-risk cohort 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. Cold Spring Harb Mol Case Stud Research Article 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 APOE 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. Cold Spring Harbor Laboratory Press 2018-12 /pmc/articles/PMC6318774/ /pubmed/30487145 http://dx.doi.org/10.1101/mcs.a003178 Text en © 2018 Rego et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted reuse and redistribution provided that the original author and source are credited.
spellingShingle Research Article
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.
High-frequency actionable pathogenic exome variants in an average-risk cohort
title High-frequency actionable pathogenic exome variants in an average-risk cohort
title_full High-frequency actionable pathogenic exome variants in an average-risk cohort
title_fullStr High-frequency actionable pathogenic exome variants in an average-risk cohort
title_full_unstemmed High-frequency actionable pathogenic exome variants in an average-risk cohort
title_short High-frequency actionable pathogenic exome variants in an average-risk cohort
title_sort high-frequency actionable pathogenic exome variants in an average-risk cohort
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318774/
https://www.ncbi.nlm.nih.gov/pubmed/30487145
http://dx.doi.org/10.1101/mcs.a003178
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