Department of Pediatrics, Section of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas.
Department of Pediatrics, Section of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas.
Heart Rhythm. 2018 Jul;15(7):1042-1050. doi: 10.1016/j.hrthm.2018.02.031. Epub 2018 Mar 2.
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.
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."
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.
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.
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.
由于临床基因检测的快速扩张，越来越多具有不确定意义和诊断价值的遗传变异在儿童中被发现。在与遗传性通道病相关的基因中发现的变异，如长 QT 综合征（LQTS），由于与病理性突变相关的心脏性猝死风险，尤其难以解释。
本研究旨在确定来自全外显子组测序（WES）的 LQTS 相关基因中的变异是否代表疾病相关的生物标志物或背景遗传“噪声”。
从 Baylor 遗传学实验室获得 17 个 LQTS 相关基因的 WES 变异。从 GnomAD 数据库获得健康对照的稀有变异。从文献中提取 LQTS 病例变异。进行氨基酸水平的映射和信噪比计算。分析在我们机构评估的 WES 受试者的临床病史和诊断研究。
在 7244 名 WES 先证者中，有 38.3%的人存在 LQTS 病例相关基因中的变异。在 WES 和健康队列中，LQTS1-3（分别为 11.2%和 12.9%）和 LQTS4-17（分别为 27.1%和 38.4%）的变异频率相似。WES 变异优先定位于与病例相比在对照个体中改变的氨基酸。基于氨基酸水平分析，WES 鉴定的变异与健康背景变异无法区分，而 LQTS1 和 2 病例鉴定的变异定位于明确的病理性“热点”。没有经过临床评估的个体有 LQTS 的临床怀疑。
在 WES 测试中，偶然发现的 LQTS 相关变异的患病率约为 38%。这些变异很可能代表良性的健康背景遗传变异，而不是疾病相关的突变。
