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.
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2018-07
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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.
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Landstrom, Andrew P, Ernesto Fernandez, Jill A Rosenfeld, Yaping Yang, Andrew L Dailey-Schwartz, Christina Y Miyake, Hugh D Allen, Daniel J Penny, et al. (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.
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Andrew Paul Landstrom
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, and short QT syndrome. He also specializes in the evaluation of children following a cardiac arrest or after the sudden and unexplained death of a family member. He has expertise in cardiovascular genetics and uses it to identify individuals in a family who may be at risk of a disease, even if all clinical testing is negative. As a scientist, he is trained in genetics and cell biology. He runs a research lab exploring the genetic and molecular causes of arrhythmias, sudden unexplained death syndromes, and heart muscle disease (cardiomyopathies). He utilizes patient-derived induced pluripotent stem cells and genetic mouse models to identify the mechanisms of cardiovascular genetic disease with the goal of developing novel therapies.
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