Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, University of Sydney, Sydney, NSW, Australia; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, NSW, Australia; St George's University of London, London, United Kingdom.
Department of Cardiology, Ege University School of Medicine, Izmir, Turkey.
Heart Rhythm. 2018 Jul;15(7):1051-1057. doi: 10.1016/j.hrthm.2018.03.015. Epub 2018 May 11.
There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS).
We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity.
Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria.
A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 ± 7 ms vs 165 ± 9 ms; P = .83), QRS duration (101 ± 6 ms vs 89 ± 5 ms; P = .35), or corrected QT interval (414 ± 35 ms vs 405 ± 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant.
The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS.
目前仅有有限的证据表明 Brugada 综合征（BrS）是由 SCN1B 变异（BrS5）引起的。这种基因可能不恰当地包含在 BrS 或心律失常性晕厥综合征（SADS）的常规基因检测面板中。
我们旨在对具有报道称致病性 SCN1B 变异的 BrS 和 SADS 家族进行基因型-表型相关性分析，并对其致病性进行综述。
从全球 6 个遗传性心律失常中心评估具有 BrS 和 SADS 的家族，并进行全面的文献综述。研究了临床特征，包括相关病史、心电图参数和药物激发试验结果。使用美国医学遗传学学院标准重新分类 SCN1B 基因检测结果。
从 8 个家系中确定了 23 名 SCN1B 基因型阳性个体。4 名先证者（17%）在就诊时发生心室颤动或心源性猝死。所有家族成员均无晕厥或室性心律失常。23 名基因型阳性个体中仅有 2 名（9%）表现为自发性 BrS 心电图模式。87%（13/15）的 BrS 药物激发试验为阴性。基因型阳性和阴性家族成员的 PR 间期（161±7 ms 与 165±9 ms；P=0.83）、QRS 时限（101±6 ms 与 89±5 ms；P=0.35）或校正 QT 间期（414±35 ms 与 405±8 ms；P=0.7）无差异。在基因组聚集数据库浏览器中，先前报道的 SCN1B 变异的总体频率为 0.004%，超过了由于 SCN1B 引起的 BrS 的估计患病率（0.0005%），包括 23 名个体中的 15 名（65%）存在 p.Trp179X 变异。
家族间基因型-表型不一致，加上基因组聚集数据库浏览器中先前报道的突变频率较高，表明 SCN1B 不是 BrS 或 SADS 的单一基因病因。
