Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise.
Abstract
BACKGROUND:Due to rapid expansion of clinical genetic testing, an increasing number
of genetic variants of undetermined significance and unclear diagnostic value are
being identified in children. Variants found in genes associated with heritable channelopathies,
such as long QT syndrome (LQTS), are particularly difficult to interpret given the
risk of sudden cardiac death associated with pathologic mutations. OBJECTIVE:The purpose
of this study was to determine whether variants in LQTS-associated genes from whole
exome sequencing (WES) represent disease-associated biomarkers or background genetic
"noise." METHODS:WES variants from Baylor Genetics Laboratories were obtained for
17 LQTS-associated genes. Rare variants from healthy controls were obtained from the
GnomAD database. LQTS case variants were extracted from the literature. Amino acid-level
mapping and signal-to-noise calculations were conducted. Clinical history and diagnostic
studies were analyzed for WES subjects evaluated at our institution. RESULTS:Variants
in LQTS case-associated genes were present in 38.3% of 7244 WES probands. There was
a similar frequency of variants in the WES and healthy cohorts for LQTS1-3 (11.2%
and 12.9%, respectively) and LQTS4-17 (27.1% and 38.4%, respectively). WES variants
preferentially localized to amino acids altered in control individuals compared to
cases. Based on amino acid-level analysis, WES-identified variants are indistinguishable
from healthy background variation, whereas LQTS1 and 2 case-identified variants localized
to clear pathologic "hotspots." No individuals who underwent clinical evaluation had
clinical suspicion for LQTS. CONCLUSION:The prevalence of incidentally identified
LQTS-associated variants is ∼38% among WES tests. These variants most likely represent
benign healthy background genetic variation rather than disease-associated mutations.
Type
Journal articleSubject
HumansLong QT Syndrome
Genetic Predisposition to Disease
Amino Acids
DNA
DNA Mutational Analysis
Phenotype
Mutation
Adolescent
Child
Female
Male
Genetic Variation
Genetic Testing
Exome
Whole Exome Sequencing
Permalink
https://hdl.handle.net/10161/20298Published Version (Please cite this version)
10.1016/j.hrthm.2018.02.031Publication Info
Landstrom, Andrew P; Fernandez, Ernesto; Rosenfeld, Jill A; Yang, Yaping; Dailey-Schwartz,
Andrew L; Miyake, Christina Y; ... Kim, Jeffrey J (2018). Amino acid-level signal-to-noise analysis of incidentally identified variants in genes
associated with long QT syndrome during pediatric whole exome sequencing reflects
background genetic noise. Heart rhythm, 15(7). pp. 1042-1050. 10.1016/j.hrthm.2018.02.031. Retrieved from https://hdl.handle.net/10161/20298.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
More Info
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,

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