BACKGROUND:A pathogenic/likely pathogenic variant can be found in 20% to 25% of patients with Brugada syndrome (BrS) and a pathogenic/likely pathogenic variant in SCN5A is associated with a worse prognosis. The aim of this study is to define the diagnostic yield of a large gene panel with American College of Medical Genetics and Genomics variant classification and to assess prognosis of SCN5A and non-SCN5A variants.METHODS:All patients with BrS, were prospectively enrolled in the Universitair Ziekenhuis Brussel registry between 1992 and 2022. Inclusion criteria for the study were (1) BrS diagnosis; (2) genetic analysis performed with a large gene panel; (3) classification of variants following American College of Medical Genetics and Genomics guidelines. Patients with a pathogenic/likely pathogenic variant in SCN5A were defined as SCN5A⁺. Patients with a reported variant in a non-SCN5A gene or with no reported variants were defined as patients with SCN5A⁻. All variants were classified as missense or predicted loss of function.RESULTS:A total of 500 BrS patients were analyzed. A total of 104 patients (20.8%) were SCN5A⁺ and 396 patients (79.2%) were SCN5A⁻. A non-SCN5A gene variant was found in 75 patients (15.0%), of whom, 58 patients (77.3%) had a missense variant and 17 patients (22.7%) had a predicted loss of function variant. At a follow-up of 84.0 months, 48 patients (9.6%) experienced a ventricular arrhythmia (VA). Patients without any variant had higher VA-free survival, compared with carriers of a predicted loss of function variant in SCN5A⁺ or non-SCN5A genes. There was no difference in VA-free survival between patients without any variant and missense variant carriers in SCN5A⁺ or non-SCN5A genes. At Cox analysis, SCN5A⁺ or non-SCN5A predicted loss of function variant was an independent predictor of VA.CONCLUSIONS:In a large BrS cohort, the yield for SCN5A⁺ is 20.8%. A predicted loss of function variant carrier is an independent predictor of VA.

中文翻译：

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布鲁格达综合症的基因检测：30 年的经验

背景：20% 至 25% 的 Brugada 综合征 (BrS) 患者中可发现致病性/可能致病性变异，SCN5A 中的致病性/可能致病性变异与较差的预后相关。本研究的目的是确定美国医学遗传学和基因组学学院变异分类的大型基因组的诊断率，并评估 SCN5A 和非 SCN5A 变异的预后。 方法：所有 BrS 患者均前瞻性纳入研究Universitair Ziekenhuis Brussel 1992 年至 2022 年间的登记。该研究的纳入标准是 (1) BrS 诊断； (2) 使用大型基因组进行遗传分析； (3) 遵循美国医学遗传学和基因组学学院指南的变异分类。 SCN5A 具有致病性/可能致病性变异的患者被定义为 SCN5A ⁺。报告有非 SCN5A基因变异或没有报告变异的患者被定义为 SCN5A ^-患者。所有变异均被分类为错义或预测功能丧失。 结果：总共分析了 500 名 BrS 患者。共有 104 名患者 (20.8%) 为 SCN5A ⁺，396 名患者 (79.2%) 为 SCN5A ^-。在 75 名患者（15.0%）中发现非 SCN5A基因变异，其中 58 名患者（77.3%）存在错义变异，17 名患者（22.7%）存在预测功能丧失变异。在 84.0 个月的随访中，48 名患者 (9.6%) 出现室性心律失常 (VA)。与SCN5A ⁺或非SCN5A基因中预测功能丧失变异的携带者相比，没有任何变异的患者具有更高的无 VA 生存率。无SCN5A ⁺或非SCN5A基因变异和错义变异携带者之间的无VA生存率没有差异。在 Cox 分析中，SCN5A ⁺或非 SCN5A 预测的功能丧失变异是 VA 的独立预测因子。结论：在大型 BrS 队列中，SCN5A ⁺的产率为20.8%。预测的功能丧失变异携带者是 VA 的独立预测因子。