Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to cause these conditions, but evidence supporting these gene–disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes. Methods and results Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3). Conclusions Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.

中文翻译：

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心律失常性猝死中 CPVT 和短 QT 综合征的基因有效性评估

目的 儿茶酚胺能多形性室性心动过速 (CPVT) 和短 QT 综合征 (SQTS) 是遗传性心律失常性疾病，可导致猝死。据报道，许多基因会导致这些疾病，但支持这些基因与疾病关系的证据差异很大。为了确保正确利用 CPVT 和 SQTS 患者的遗传信息，我们对先前报道的基因进行了基于证据的重新评估。方法和结果 三个团队使用 ClinGen 基因管理框架独立管理了 11 个 CPVT 和 9 个 SQTS 相关基因的所有已发表证据。结果由通道病专家小组审查并提供最终分类。7 个基因具有明确至中等程度的 CPVT 致病原因证据，具有常染色体显性遗传（RYR2、CALM1、CALM2、CALM3）或常染色体隐性遗传（CASQ2、TRDN、TECRL）。CPVT 的四个有争议基因（KCNJ2、PKP2、SCN5A）中的三个被专家小组认为所报告的表型不代表 CPVT，而报告的第四个基因 (ANK2) 的变异在人群中太常见而无法报告。会引起疾病。对于 SQTS，只有一个基因 (KCNH2) 被归类为确定基因，其他三个基因（KCNQ1、KCNJ2、SLC4A3）具有强到中度的证据。SQTS 基因的大部分遗传证据来自极少数变异（KCNJ2 中有 5 个，KCNH2 中有 2 个，KCNQ1/SLC4A3 中有 1 个）。结论 7 个 CPVT 和 4 个 SQTS 基因具有疾病因果关系的有效证据，应纳入基因检测组。与可能模拟 CPVT/SQTS 临床特征的病症相关的其他基因对于鉴别诊断具有潜在的实用性。