ArticleHeart rhythm2018
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.
Article in Heart rhythm, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 15 citations in OpenAlex.
- Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.Journal of molecular and cellular cardiology · 2020Pooled it
- Promise and Peril of a Genotype-First Approach to Mendelian Cardiovascular Disease.Journal of the American Heart Association · 2024Review
- Article
- Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy-Associated Genes.Journal of the American Heart Association · 2022Article
- From diagnostic testing to precision medicine: the evolving role of genomics in cardiac channelopathies and cardiomyopathies in children.Current opinion in genetics & development · 2022Review
- Signal-to-Noise Analysis Can Inform the Likelihood That Incidentally Identified Variants in Sarcomeric Genes Are Associated with Pediatric Cardiomyopathy.Journal of personalized medicine · 2022Article
- GENESIS: Gene-Specific Machine Learning Models for Variants of Uncertain Significance Found in Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome-Associated Genes.Circulation. Arrhythmia and electrophysiology · 2022Article
- Interpretation of Incidental Genetic Findings Localizing to Genes Associated With Cardiac Channelopathies and Cardiomyopathies.Circulation. Genomic and precision medicine · 2021Article
- Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally IdentifiedCirculation. Genomic and precision medicine · 2021Article
- Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.Scientific reports · 2019Article
- Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.Molecular genetics & genomic medicine · 2019Article
- Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation.Journal of visualized experiments : JoVE · 2019Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundDue 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.
objectiveThe 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."
methodsWES 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.
resultsVariants 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.
conclusionThe 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.
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