Skip to main content
Duke University Libraries
DukeSpace Scholarship by Duke Authors
  • Login
  • Ask
  • Menu
  • Login
  • Ask a Librarian
  • Search & Find
  • Using the Library
  • Research Support
  • Course Support
  • Libraries
  • About
View Item 
  •   DukeSpace
  • Duke Scholarly Works
  • Scholarly Articles
  • View Item
  •   DukeSpace
  • Duke Scholarly Works
  • Scholarly Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.

Thumbnail
View / Download
1.8 Mb
Date
2019-06
Authors
Headrick, Andrew T
Rosenfeld, Jill A
Yang, Yaping
Tunuguntla, Hari
Allen, Hugh D
Penny, Daniel J
Kim, Jeffrey J
Landstrom, Andrew P
Show More
(8 total)
Repository Usage Stats
64
views
23
downloads
Abstract
BACKGROUND:With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. METHODS:WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC-associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal-to-noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). RESULTS:Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid-level signal-to-noise analysis of cases demonstrated "pathologic hotspots" localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N-terminal cadherin-repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant-positive individuals. CONCLUSIONS:Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to "background" variants. Incidentally identified variants are unlikely to be pathologic.
Type
Journal article
Subject
arrhythmogenic right ventricular cardiomyopathy
genetic testing
genetics
incidental finding
secondary finding
variant of undetermined significance
whole exome sequencing
Permalink
https://hdl.handle.net/10161/20294
Published Version (Please cite this version)
10.1002/mgg3.593
Publication Info
Headrick, Andrew T; Rosenfeld, Jill A; Yang, Yaping; Tunuguntla, Hari; Allen, Hugh D; Penny, Daniel J; ... Landstrom, Andrew P (2019). Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation. Molecular Genetics & Genomic Medicine, 7(6). pp. e593. 10.1002/mgg3.593. Retrieved from https://hdl.handle.net/10161/20294.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
  • Scholarly Articles
More Info
Show full item record

Scholars@Duke

Landstrom

Andrew Paul Landstrom

Associate Professor of Pediatrics
Dr. Landstrom is a physician scientist who specializes in the care of children and young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained death syndromes. As a clinician, he is trained in pediatric cardiology with a focus on arrhythmias and genetic diseases of the heart.  He specializes in caring for patients with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia,
Open Access

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy

Rights for Collection: Scholarly Articles


Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info

Make Your Work Available Here

How to Deposit

Browse

All of DukeSpaceCommunities & CollectionsAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit DateThis CollectionAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit Date

My Account

LoginRegister

Statistics

View Usage Statistics
Duke University Libraries

Contact Us

411 Chapel Drive
Durham, NC 27708
(919) 660-5870
Perkins Library Service Desk

Digital Repositories at Duke

  • Report a problem with the repositories
  • About digital repositories at Duke
  • Accessibility Policy
  • Deaccession and DMCA Takedown Policy

TwitterFacebookYouTubeFlickrInstagramBlogs

Sign Up for Our Newsletter
  • Re-use & Attribution / Privacy
  • Harmful Language Statement
  • Support the Libraries
Duke University