Division of Cardiology, Toronto General Hospital and University of Toronto, Canada (A.A, M.C., M.H.G.).
Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, and Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy (V.N., E.A., S.A., D.M.).
Circulation. 2020 Feb 11;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132. Epub 2020 Jan 27.
Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
Of 17 genes reported as being causative for LQTS, 9 () were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes () were curated as definitive genes for typical LQTS. Another 4 genes () were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene () had moderate level evidence for causing LQTS.
More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
长 QT 综合征（LQTS）是最早描述和最常见的遗传性心律失常。在过去的 25 年中，已经有多个基因被报道可导致这种疾病，并且这些基因在患者中常规进行检测。由于我们对人类遗传变异的理解发生了重大变化，因此需要重新评估 LQTS 的报告遗传原因。
利用基于证据的框架，3 个基因审核团队在彼此不知情的情况下，对报道可导致 LQTS 的 17 个基因的证据水平进行评分。一个临床领域通道病工作组在评估独立审核团队评分的证据后，对这些基因进行了最终分类，以确定它们是否为 LQTS 的致病原因。
在报道为导致 LQTS 的 17 个基因中，有 9 个（）被归类为具有有限或有争议的证据作为 LQTS 致病基因。仅有 3 个基因（）被确认为典型 LQTS 的明确基因。另外 4 个基因（）被发现具有强烈或明确的证据表明其因果关系与非典型特征的 LQTS，包括新生儿房室传导阻滞。其余的基因（）具有导致 LQTS 的中度证据水平。
超过一半报道为导致 LQTS 的基因的疾病因果关系的证据有限或有争议。除非伴有新的、充分的遗传证据，否则这些基因中的遗传变异不应用于临床决策。这些发现表明，缺乏支持基因-疾病关联的证据可能会扩展到医学的其他学科，并需要对以前报道的致病基因进行当代基于证据的评估，以确保它们在精准医学中的合理使用。
