Background:Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations.Methods:Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).Results:In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P=0.0078). Among SCN5A-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P=0.0846). In SCN5A-negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P=0.0146). Among E1784K-SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P=0.0011).Conclusions:Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

中文翻译：

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SCN5A 突变类型和遗传风险评分与 SCN5A 家族中的 Brugada 综合征表型不同

背景：Brugada 综合征 (BrS) 的特征是 1 型 Brugada 心电图模式。在 20% 的 BrS 家族中发现了SCN5A 中的致病性罕见变异（突变），在这些家族中观察到不完全外显率和基因型阴性表型阳性个体。E1784K- SCN5A是最常见的SCN5A突变。我们确定的BrS遗传风险评分（BRS-GRS）和关联SCN5A突变型的表型的BrS生物圈家庭与SCN5A mutations.Methods：主题与同伙窝藏自发1型图案或正/负药品挑战SCN5A从 16 个中心 (n=312) 招募突变。在两个队列中研究了先前与 BrS 具有全基因组意义相关的单核苷酸多态性：rs11708996、rs10428132 和 rs9388451。假设了 BrS-GRS 的加性线性遗传模型（6 个单核苷酸多态性风险等位基因）。 结果：在总人群（n=312）中，BrS-GRS ≥4 个风险等位基因对 BrS 表型产生的优势比为 4.15（ [95% CI，1.45–11.85]；P = 0.0078）。在SCN5A阳性个体 (n=258) 中，BrS-GRS ≥4 个风险等位基因的优势比为 2.35（[95% CI，0.89–6.22]；P = 0.0846）。在SCN5A阴性亲属 (n=54) 中，BrS-GRS ≥4 个等位基因的优势比为 22.29 ([95% CI, 1.84–269.30]; P=0.0146）。在 E1784K- SCN5A阳性家族成员 (n=79) 中，宿主≥4 个风险等位基因的优势比为 5.12（[95% CI，1.93–13.62]；P = 0.0011）。结论：常见的遗传变异与可变表达相关SCN5A家族中 BrS 表型的差异，部分解释了不完全外显率和基因型阴性表型阳性个体。SCN5A突变基因型和 BrS-GRS 与 BrS 表型相关，但关联强度根据SCN5A突变的存在和功能丧失的严重程度而变化。