Division of Cardiology, University of British Columbia, 1033 Davie St., Rm 211, Vancouver, BC, Canada.
Cardiology Department, Royal Papworth Hospital, Cambridge, UK.
Europace. 2019 Nov 1;21(11):1725-1732. doi: 10.1093/europace/euz215.
Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits.
Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise.
The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.
CACAN1C 中的致病性获得性功能变异导致 8 型长 QT 综合征（LQT8）。我们旨在描述 LQT8 的心电图特征，并利用分子建模深入了解其遗传罪魁祸首。
从遗传检测实验室鉴定 CACNA1C 的罕见变异。治疗医生提供临床信息。根据最新指南独立评估变异的致病性。将致病性（P）和可能致病性（LP）变体映射到 Cav1.2 蛋白的 3D 模型结构上。从 19 个非综合征性 LQTS 家族的 23 名患者中鉴定出 9 个 P/LP 变体。在 79%的家族中发现的 6 个变体聚集在细胞溶质 II-III 环区域的 4 个残基部分，该区域形成一个能够结合 STAC SH3 结构域的区域。因此，变体可能影响 SH3 结构域包含蛋白的结合。具有 II-III 环变体和其他 P/LP 变体的患者发生心律失常事件的比例相似（53%对 48%，P=0.41），尽管 QTc 间隔更短（477±31ms 对 515±37ms，P=0.03）。仅在具有 II-III 环变体的家族中报告了猝死史（60%对 0%，P=0.03）。主要的 T 波形态是晚期尖峰 T 波，具有陡峭的下降支。运动试验显示站立时 QTc 延长，运动后 4 分钟恢复时 QTc 延长。
CACNA1C 介导的 LQT8 患者的大多数 P/LP 变体聚集在细胞溶质 II-III 环的 SH3 结合域。这代表 LQT8 中的“突变热点”。常见的是晚期尖峰 T 波，具有陡峭的下降支和运动时 QT 延长。
