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.

Landstrom, Andrew P

Fernandez, Ernesto

Rosenfeld, Jill A

Yang, Yaping

Dailey-Schwartz, Andrew L

Miyake, Christina Y

Allen, Hugh D

Penny, Daniel J

Kim, Jeffrey J

2020-04-01T13:29:04Z

2020-04-01T13:29:04Z

2018-07

2020-04-01T13:29:02Z

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.

S1547-5271(18)30142-5

1547-5271

1556-3871

https://hdl.handle.net/10161/20298

eng

Elsevier BV

Heart rhythm

10.1016/j.hrthm.2018.02.031

Humans

Long 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

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.

Journal article

Landstrom, Andrew P|0000-0002-1878-9631

1042

1050

7

School of Medicine

Cell Biology

Pediatrics, Cardiology

Duke

Basic Science Departments

Pediatrics

Clinical Science Departments

Published

15