Department of Cardiology, Aarhus University Hospital, Aarhus N, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark.
Heart Rhythm. 2023 Aug;20(8):1136-1143. doi: 10.1016/j.hrthm.2023.02.010. Epub 2023 Feb 15.
A variant in the SLC4A3 anion exchanger has been identified as a novel cause of short QT syndrome (SQTS), but the clinical importance of SLC4A3 as a cause of SQTS or sudden cardiac death remains unknown.
The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients using gene panels including SLC4A3.
In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3variants was validated in a zebrafish embryo heart model.
Potentially disease-causing variants were identified in 9 (26%) patients and were mainly (15%) located in SLC4A3: 4 patients heterozygous for novel nonsynonymous SLC4A3 variants-p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His-and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1, 1× in KCNJ2, and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals (calculated using the Bazett formula) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes.
In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death.
已鉴定出 SLC4A3 阴离子交换器的变体是短 QT 综合征 (SQTS) 的新病因，但 SLC4A3 作为 SQTS 或心源性猝死病因的临床重要性仍不清楚。
本研究旨在通过包含 SLC4A3 的基因面板调查 SQTS 患者中潜在致病变异的发生率。
在这项多中心研究中，对 34 名 SQTS 指数患者进行了基因检测。在斑马鱼胚胎心脏模型中验证了新的 SLC4A3 变体的致病性。
在 9 名（26%）患者中发现了潜在的致病变异，主要位于 SLC4A3 中（15%）：4 名患者为新型非同义 SLC4A3 变异杂合子-p.Arg600Cys、p.Arg621Trp、p.Glu852Asp 和 p.Arg952His-和 1 名患者为已知的 p.Arg370His 变异。在其他 SQTS 基因中，潜在的致病变异较少见（KCNQ1 中 2 例，KCNJ2 中 1 例，CACNA1C 中 1 例）。SLC4A3 变异携带者（n=5）的心率相似，但 QT 和 J 点至 T 波峰间期较短，而非携带者（n=29）。斑马鱼中 slc4a3 的敲低导致心率校正 QT 间期（使用 Bazett 公式计算）缩短，而过表达天然人类 SLC4A3 编码蛋白（AE3）可纠正该缩短，但 p.Arg600Cys、p.Arg621Trp、p.Glu852Asp 和 p.Arg952His 突变的 AE3 变体以及 slc4a3 均不能，提示这些变异具有致病性。slc4a3/AE3 功能障碍与碱性细胞质和心肌细胞动作电位缩短有关。
在大约四分之一的 SQTS 患者中，可以发现潜在的致病变异。SLC4A3 的非同义变异是 SQTS 的最常见病因，强调在 SQTS 或心源性猝死患者的基因筛查中纳入 SLC4A3 的重要性。
