Genetic interpretation and clinical translation of minor genes related to Brugada syndrome
Genetic interpretation and clinical translation of minor genes related to Brugada syndrome
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DOI：
10.1002/humu.23730
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发表时间：
2019-06-01
期刊：
影响因子：
3.9
通讯作者：
Brugada, Ramon
中科院分区：
文献类型：
--
作者：
Campuzano, Oscar;Sarquella-Brugada, Georgia;Brugada, Ramon
布鲁格达综合征（BrS）是一种与心源性猝死相关的遗传性心律失常疾病。主要基因是SCN5A。据报道，其他 42 个基因中的其他变异是有害的，尽管这些变异尚未接受全面的致病性分析。我们的目的是阐明目前报道的所有与 BrS 相关的次要基因变异的作用。我们根据美国医学遗传学和基因组学学会指南，对与 BrS 相关的所有基因（SCN5A 除外）已发表的临床和基础数据进行了全面分析。我们的结果发现了 133 个可能与 BrS 相关的罕见变异。应用当前的建议后，只有 6 个变体 (4.51%) 显示出决定性的致病作用。所有明确的致病变异均位于编码钠通道或相关蛋白的四个基因中：SLMAP、SEMA3A、SCNN1A 和 SCN2B。总共 19 个额外基因中 33.83% 的变异具有潜在致病性。除了 SCN5A 之外，我们还得出了四个次要基因中与 BrS 相关的明确致病变异。因此，当前与 BrS 相关的基因列表应包括 SCN5A、SLMAP、SEMA3A、SCNN1A 和 SCN2B。对于目前被归类为对 BrS 潜在有害的所有变异，应进行全面的遗传解释和仔细的临床翻译。
Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.