Centro Cardiologico Monzino, IRCCS, Via C. Parea 4, Milano, 20138, Italy.
Toronto General Hospital Research Institute, University of Toronto, Toronto, Canada.
Europace. 2023 Nov 2;25(11). doi: 10.1093/europace/euad317.
Rare variants in the KCNQ1 gene are found in the healthy population to a much greater extent than the prevalence of Long QT Syndrome type 1 (LQTS1). This observation creates challenges in the interpretation of KCNQ1 rare variants that may be identified as secondary findings in whole exome sequencing.This study sought to identify missense variants within sub-domains of the KCNQ1-encoded Kv7.1 potassium channel that would be highly predictive of disease in the context of secondary findings.
We established a set of KCNQ1 variants reported in over 3700 patients with diagnosed or suspected LQTS sent for clinical genetic testing and compared the domain-specific location of identified variants to those observed in an unselected population of 140 000 individuals. We identified three regions that showed a significant enrichment of KCNQ1 variants associated with LQTS at an odds ratio (OR) >2: the pore region, and the adjacent 5th (S5) and 6th (S6) transmembrane (TM) regions. An additional segment within the carboxyl terminus of Kv7.1, conserved region 2 (CR2), also showed an increased OR of disease association. Furthermore, the TM spanning S5-Pore-S6 region correlated with a significant increase in cardiac events.
Rare missense variants with a clear phenotype of LQTS have a high likelihood to be present within the pore and adjacent TM segments (S5-Pore-S6) and a greater tendency to be present within CR2. This data will enhance interpretation of secondary findings within the KCNQ1 gene. Further, our data support a more severe phenotype in LQTS patients with variants within the S5-Pore-S6 region.
在健康人群中，KCNQ1 基因的罕见变异比 1 型长 QT 综合征（LQTS1）的患病率更为常见。这一观察结果给 KCNQ1 罕见变异的解释带来了挑战，这些变异可能被认为是外显子组测序中的次要发现。本研究旨在确定 KCNQ1 编码 Kv7.1 钾通道亚域内的错义变异，这些变异在次要发现的情况下对疾病具有高度预测性。
我们建立了一组在超过 3700 名被诊断或疑似患有 LQTS 并接受临床基因检测的患者中报告的 KCNQ1 变体，并将鉴定出的变体的特定域位置与在未选择的 140000 名个体中观察到的变体进行了比较。我们发现了三个区域，其中 KCNQ1 变体与 LQTS 的相关性显著富集，比值比（OR）>2：孔区，以及相邻的第 5（S5）和第 6（S6）跨膜（TM）区。Kv7.1 羧基末端的另一个片段，保守区 2（CR2），也显示出疾病相关性的 OR 增加。此外，跨越 S5-孔-S6 区的 TM 与心脏事件的显著增加相关。
具有明确 LQTS 表型的罕见错义变异极有可能存在于孔和相邻的 TM 区域（S5-孔-S6）中，并且更有可能存在于 CR2 中。这些数据将增强对 KCNQ1 基因中次要发现的解释。此外，我们的数据支持在 S5-孔-S6 区域内存在变异的 LQTS 患者具有更严重的表型。
