KCNJ2基因编码内向整流Kir2.1通道,保持静息电位和细胞兴奋性。大概,突变携带者的临床表型与离子通透性缺陷相关。功能缺失突变导致QTc延长,具有可变的异形特征,而功能获得突变导致短QT综合征和/或心房颤动。
我们筛选了210名长QT综合征的先证者的KCNJ2基因突变。在转染的CHO-K1细胞中对p.Val93Ile变体进行电生理学研究。
我们发现了三种罕见的遗传变异,p.Arg67Trp,p.Val93Ile,和p.R218Q,在三个不相关的LQTS先证中。具有p.Arg67Trp和p.R218Q的前带具有典型的Andersen-Tawil(ATS)表型,p.Val93Ile载体有单独的QTc延长。变异p.Val93Ile最初被描述为导致家族性心房颤动的功能获得性致病性突变。我们在CHO-K1细胞中验证了这种变体的电生理特征,但这些患者的家属没有房颤。使用ACMG(2015)标准,我们将该变异体重新评估为意义未知的变异体(III类).
LQT7在俄罗斯是一种罕见的LQTS,占LQTS队列的1%。变异p.Val93Ile导致不同细胞系中的功能增益效应,但是它的临床表现并不那么一致。这种变异的临床意义可能被高估了。
The KCNJ2 gene encodes inward rectifier Kir2.1 channels, maintaining resting potential and cell excitability. Presumably, clinical phenotypes of mutation carriers correlate with ion permeability defects. Loss-of-function mutations lead to QTc prolongation with variable dysmorphic features, whereas gain-of-function mutations cause short QT syndrome and/or atrial fibrillation.
We screened 210 probands with Long QT syndrome for mutations in the KCNJ2 gene. The electrophysiological study was performed for the p.Val93Ile variant in the transfected CHO-K1 cells.
We found three rare genetic variants, p.Arg67Trp, p.Val93Ile, and p.R218Q, in three unrelated LQTS probands. Probands with p.Arg67Trp and p.R218Q had a phenotype typical for Andersen-Tawil (ATS), and the p.Val93Ile carrier had lone QTc prolongation. Variant p.Val93Ile was initially described as a gain-of-function pathogenic mutation causing familial atrial fibrillation. We validated electrophysiological features of this variant in CHO-K1 cells, but no family members of these patients had atrial fibrillation. Using ACMG (2015) criteria, we re-assessed this variant as a variant of unknown significance (class III).
LQT7 is a rare form of LQTS in Russia, and accounts for 1% of the LQTS cohort. Variant p.Val93Ile leads to a gain-of-function effect in the different cell lines, but its clinical appearance is not so consistent. The clinical significance of this variant might be overestimated.