Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Chaoyang, Beijing, China.
Ann Hum Genet. 2020 Mar;84(2):161-168. doi: 10.1111/ahg.12359. Epub 2019 Nov 7.
KCNQ1, KCNH2, and SCN5A are the most common genes responsible for long QT syndrome and Brugada syndrome. However, the genetic variant frequencies of the three genes in different Chinese disease cohorts are largely unknown. In this study, we analyzed the genetic variants of KCNQ1, KCNH2, and SCN5A in patients from seven cohorts (total N = 11945, including patients clinically suspected to have inherited arrhythmia [n = 122], other cardiovascular diseases [n = 1045], epilepsy [n = 4797], or other diseases [n = 5841], and healthy controls [n = 140]) who had undergone genetic testing. All of these variants were identified via genetic testing by two Chinese companies using the Hi-Seq 2000 platform. A total of 1018 variants (minor allele frequency <0.01) were identified, with 186 (18%), 374 (37%), and 458 (46%) variants in the coding exons of KCNQ1, KCNH2, and SCN5A, respectively. Of these variants, 84% had unknown or uncertain clinical significance. The frequency of identified ClinVar pathological/likely pathological variants was higher for KCNQ1 (13/186, 7.0%) than for KCNH2 (6/374, 1.6%) or SCN5A (10/458, 2.2%), and KCNH2 held the highest number and proportion of radical mutations (30/374, 8%). The prevalence of variants was highest in the inherited arrhythmia cohort (35%) and lowest in the healthy controls (<4%), as expected. Noticeably, the variant prevalence was relatively high in the epilepsy cohort (27%). Finally, only 22 of the 82 variants (26%) identified by both companies had consistent interpretations of pathogenicity between the two companies. Our study demonstrated a comprehensive spectrum of variants in KCNQ1, KCNH2, and SCN5A in a large number of Chinese individuals, including inherited arrhythmia, cardiovascular diseases, and epilepsy. The detailed variant frequency data of each cohort could serve as a valuable reference to facilitate further variant classification by others. We also found that the interpretations of pathogenicity differed greatly among the companies.
KCNQ1、KCNH2 和 SCN5A 是导致长 QT 综合征和 Brugada 综合征的最常见基因。然而，这三个基因在不同中国疾病队列中的遗传变异频率在很大程度上尚不清楚。在这项研究中，我们分析了来自七个队列的 KCNQ1、KCNH2 和 SCN5A 的遗传变异，这些队列的患者总数为 11945 例，包括临床上疑似遗传性心律失常（n=122）、其他心血管疾病（n=1045）、癫痫（n=4797）或其他疾病（n=5841）以及健康对照组（n=140）。所有这些变异均通过两家中国公司使用 Hi-Seq 2000 平台进行的基因检测来识别。共发现 1018 个变异（次要等位基因频率<0.01），其中 KCNQ1、KCNH2 和 SCN5A 的编码外显子中分别有 186（18%）、374（37%）和 458（46%）个变异。这些变异中，84%的变异具有未知或不确定的临床意义。KCNQ1 中发现的 ClinVar 病理性/可能病理性变异的频率高于 KCNH2（13/186，7.0%）或 SCN5A（10/458，2.2%），KCNH2 具有最多数量和比例的激进突变（30/374，8%）。在遗传性心律失常队列中，变异的发生率最高（35%），而在健康对照组中最低（<4%），这是意料之中的。值得注意的是，在癫痫队列中，变异的发生率相对较高（27%）。最后，两家公司共发现了 82 个变异（26%），其中只有 22 个变异在两家公司之间的致病性解释一致。我们的研究在大量中国个体中展示了 KCNQ1、KCNH2 和 SCN5A 的全面变异谱，包括遗传性心律失常、心血管疾病和癫痫。每个队列的详细变异频率数据可以作为其他人进行进一步变异分类的宝贵参考。我们还发现，不同公司之间的致病性解释有很大差异。
