Vanderbilt University School of Medicine, Medical Scientist Training Program, Vanderbilt University, Nashville, TN.
Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Vanderbilt University Medical Center, Nashville, TN.
Genet Med. 2022 Jun;24(6):1238-1248. doi: 10.1016/j.gim.2022.02.010. Epub 2022 Mar 16.
Up to 30% of patients with Brugada syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel gene SCN5A encoding for the protein Na1.5. Recent studies suggested that Na1.5 can dimerize, and some variants exert dominant negative effects. In this study, we sought to explore the generality of missense variant Na1.5 dominant negative effects and their clinical severity.
We identified 35 LoF variants (<10% of wild type [WT] peak current) and 15 partial LoF variants (10%-50% of WT peak current) that we assessed for dominant negative effects. SCN5A variants were studied in HEK293T cells, alone or in heterozygous coexpression with WT SCN5A using automated patch clamp. To assess the clinical risk, we compared the prevalence of dominant negative vs putative haploinsufficient (frameshift, splice, or nonsense) variants in a BrS consortium and the Genome Aggregation Database population database.
In heterozygous expression with WT, 32 of 35 LoF and 6 of 15 partial LoF variants showed reduction to <75% of WT-alone peak current, showing a dominant negative effect. Individuals with dominant negative LoF variants had an elevated disease burden compared with the individuals with putative haploinsufficient variants (2.7-fold enrichment in BrS cases, P = .019).
Most SCN5A missense LoF variants exert a dominant negative effect. This class of variant confers an especially high burden of BrS.
多达 30%的 Brugada 综合征（BrS）患者携带编码心肌钠通道蛋白 Na1.5 的心脏钠离子通道基因 SCN5A 的功能丧失（LoF）变异。最近的研究表明，Na1.5 可以二聚化，并且一些变体具有显性负效应。在这项研究中，我们试图探讨错义变异 Na1.5 显性负效应及其临床严重程度的普遍性。
我们鉴定了 35 个 LoF 变异体（<10%野生型 [WT] 峰电流）和 15 个部分 LoF 变异体（10%-50% WT 峰电流），我们评估了它们的显性负效应。使用自动贴片钳，在 HEK293T 细胞中单独或与 WT SCN5A 异源共表达研究 SCN5A 变异体。为了评估临床风险，我们比较了 BrS 联合和基因组聚集数据库人群数据库中显性负变与推测的杂合功能不全（移码、剪接或无义）变体的患病率。
在与 WT 的杂合表达中，35 个 LoF 中的 32 个和 15 个部分 LoF 中的 6 个显示峰电流降低至<75% WT- 单独，表现出显性负效应。与推测的杂合功能不全变体相比，具有显性负 LoF 变体的个体具有更高的疾病负担（BrS 病例的 2.7 倍富集，P=0.019）。
大多数 SCN5A 错义 LoF 变体具有显性负效应。这种变异类别的 BrS 负担特别高。
