Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.
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 articleSubject
arrhythmogenic right ventricular cardiomyopathygenetic testing
genetics
incidental finding
secondary finding
variant of undetermined significance
whole exome sequencing
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https://hdl.handle.net/10161/20294Published Version (Please cite this version)
10.1002/mgg3.593Publication 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.
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Show full item recordScholars@Duke
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,

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