Center of Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Medical Genetics (MEDGEN), GENCOR, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Orphanet J Rare Dis. 2023 Jan 31;18(1):23. doi: 10.1186/s13023-023-02618-4.
The c.1124_1127delTTCA p.(Ile375Argfs*43) pathogenic variant is the most frequently identified molecular defect in the KCNQ1 gene in the cardiogenetics clinic of the Antwerp University Hospital. This variant was observed in nine families presenting with either Jervell-Lange-Nielsen syndrome or long QT syndrome (LQTS). Here, we report on the molecular, clinical and functional characterization of the KCNQ1 c.1124_1127delTTCA variant.
Forty-one heterozygous variant harboring individuals demonstrated a predominantly mild clinical and electrophysiological phenotype, compared to individuals harboring other KCNQ1 pathogenic variants (5% symptomatic before 40 years of age, compared to 24% and 29% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers, respectively, 33% with QTc ≤ 440 ms compared to 10% in p.(Tyr111Cys) and p.(Ala341Val) variant carriers). The LQTS phenotype was most comparable to that observed for the Swedish p.(Arg518*) founder mutation (7% symptomatic at any age, compared to 17% in p.(Arg518*) variant carriers, 33% with QTc ≤ 440 ms compared to 16% in p.(Arg518*) variant carriers). Surprisingly, short tandem repeat analysis did not reveal a common haplotype for all families. One KCNQ1 c.1124_1127delTTCA harboring patient was diagnosed with Brugada syndrome (BrS). The hypothesis of a LQTS/BrS overlap syndrome was supported by electrophysiological evidence for both loss-of-function and gain-of-function (acceleration of channel kinetics) in a heterologous expression system. However, BrS phenotypes were not identified in other affected individuals and allelic KCNQ1 expression testing in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) showed nonsense mediated decay of the c.1124_1127delTTCA allele.
The c.1124_1127delTTCA frameshift variant shows a high prevalence in our region, despite not being confirmed as a founder mutation. This variant leads to a mild LQTS phenotype in the heterozygous state. Despite initial evidence for a gain-of-function effect based on in vitro electrophysiological assessment in CHO cells and expression of the KCNQ1 c.1124_1127delTTCA allele in patient blood cells, additional testing in iPSC-CMs showed lack of expression of the mutant allele. This suggests haploinsufficiency as the pathogenic mechanism. Nonetheless, as inter-individual differences in allele expression in (iPSC-) cardiomyocytes have not been assessed, a modifying effect on the BrS phenotype through potassium current modulation cannot be excluded.
在安特卫普大学医院的心脏遗传学诊所中，c.1124_1127delTTCA p.(Ile375Argfs*43) 致病性变异是 KCNQ1 基因中最常发现的分子缺陷。该变体在 9 个家族中被观察到，这些家族表现为杰尔维伦-朗格-尼尔森综合征或长 QT 综合征 (LQTS)。在这里，我们报告了 KCNQ1 c.1124_1127delTTCA 变体的分子、临床和功能特征。
41 名携带杂合变异体的个体表现出主要是轻度的临床和电生理表型，与携带其他 KCNQ1 致病性变异体的个体相比（<40 岁前无症状的 5%，与 p.(Tyr111Cys) 和 p.(Ala341Val) 变异体携带者相比分别为 24%和 29%，33%的 QTc≤440ms，与 p.(Tyr111Cys) 和 p.(Ala341Val) 变异体携带者相比为 10%）。LQTS 表型最类似于瑞典 p.(Arg518*) 创始突变观察到的表型（任何年龄无症状的 7%，与 p.(Arg518*) 变异体携带者相比为 17%，33%的 QTc≤440ms，与 p.(Arg518*) 变异体携带者相比为 16%）。令人惊讶的是，短串联重复分析并没有为所有家庭发现共同的单倍型。一名携带 KCNQ1 c.1124_1127delTTCA 的患者被诊断为 Brugada 综合征 (BrS)。电生理证据表明该变体在异源表达系统中具有功能丧失和功能获得（通道动力学加速），支持 LQTS/BrS 重叠综合征的假说。然而，在其他受影响的个体中并未发现 BrS 表型，并且在患者特异性诱导多能干细胞衍生的心肌细胞 (iPSC-CMs) 中的等位基因 KCNQ1 表达测试表明 c.1124_1127delTTCA 等位基因的无义介导衰减。
尽管未被确认为创始突变，但 c.1124_1127delTTCA 移码变体在我们的地区具有很高的流行率。该变体在杂合状态下导致轻度 LQTS 表型。尽管最初基于 CHO 细胞中的体外电生理评估和患者血液细胞中 KCNQ1 c.1124_1127delTTCA 等位基因的表达获得了功能增益效应的证据，但在 iPSC-CMs 中的进一步测试显示突变等位基因缺乏表达。这表明杂合不足是致病机制。尽管如此，由于尚未评估（iPSC-）心肌细胞中等位基因表达的个体间差异，不能排除通过钾电流调节对 BrS 表型的修饰作用。
