Giladi Moshe, Chorin Odelia, Piccirillo Silvia, Prass Elon, Reznik Wolf Haike, Shamash Jana, Haimovich Ariela, Barel Ortal, Viskin Dana, Frydman Shir, Rosso Raphael, Banai Shmuel, Viskin Sami, Chorin Ehud
Internal Medicine Division, Department of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel.
School of Medicine, Tel Aviv University, Tel Aviv, Israel; Danek Gertner Institute of Human Genetics, Tel Hashomer, Israel; Institute of Rare Diseases, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel.
JACC Clin Electrophysiol. 2025 Jul;11(7):1583-1594. doi: 10.1016/j.jacep.2025.03.027. Epub 2025 May 28.
Congenital short-QT syndrome (SQTS) is a genetic disorder characterized by short QT interval on electrocardiography (ECG) and a high risk for malignant ventricular tachyarrhythmias.
The aim of this study was to describe a new variant in the SQTS-associated gene SLC4A3 at the molecular and clinical levels.
Using whole-exome sequencing, a novel missense variant in SLC4A3 was identified, encoding for the cardiac anion exchanger 3. The mutant was characterized using computational structural modeling and functional transport studies in human embryonic kidney 293 cells. Patients were assessed using resting ECG, 12-lead Holter recordings, and a novel diagnostic test termed here the Ippon test.
A novel heterozygous SLC4A3 variant (p.R1016G) was detected in a family with 6 cases of sudden cardiac death and a case of documented polymorphic ventricular tachycardia in 5 generations. Functional analyses in human embryonic kidney 293 cells revealed gain of function rather than the loss of function expected on the basis of previously reported SQTS-associated SLC4A3 variants. Although affected family members exhibited shorter corrected QT intervals on resting ECG compared with nonaffected members (360 ± 20 ms vs 380 ± 30 ms; P = 0.0068) and 12-lead Holter monitoring (350 ± 20 ms vs 380 ± 30 ms; P = 0.0013), significant overlap existed. The sudden heart rate deceleration provoked by the Ippon test revealed that the QT interval in carriers failed to prolong in response to the sudden bradycardia, resulting in inappropriately short corrected QT intervals, leading to a better distinction of affected from nonaffected patients (340 ± 30 ms vs 370 ± 10 ms, respectively; P = 0.0003).
SLC4A3 p.R1016G is a novel SQTS-associated variant associated with a gain-of-function effect. The Ippon test is a new provocation maneuver that identifies SQTS variant carriers with high diagnostic accuracy.
先天性短QT综合征（SQTS）是一种遗传性疾病，其特征为心电图（ECG）上QT间期缩短以及发生恶性室性快速心律失常的风险较高。
本研究旨在从分子和临床水平描述SQTS相关基因SLC4A3中的一种新变异。
通过全外显子组测序，在SLC4A3中鉴定出一种新的错义变异，该变异编码心脏阴离子交换蛋白3。使用计算结构建模和在人胚肾293细胞中的功能性转运研究对该突变体进行了表征。使用静息心电图、12导联动态心电图记录以及在此称为“一分为二试验”的一种新型诊断测试对患者进行了评估。
在一个五代中有6例心源性猝死病例和1例记录到多形性室性心动过速病例的家族中检测到一种新的杂合SLC4A3变异（p.R1016G）。在人胚肾293细胞中的功能分析显示功能增强，而非基于先前报道的与SQTS相关的SLC4A3变异所预期的功能丧失。尽管与未受影响的家庭成员相比，受影响的家庭成员在静息心电图上的校正QT间期较短（360±20毫秒对380±30毫秒；P = 0.0068），并且在12导联动态心电图监测中也是如此（350±20毫秒对380±30毫秒；P = 0.0013），但存在显著重叠。“一分为二试验”引发的突然心率减速显示，携带者的QT间期在突然心动过缓时未能延长，导致校正QT间期过短，从而能更好地区分受影响和未受影响的患者（分别为340±30毫秒对370±10毫秒；P = 0.0003）。
SLC4A3 p.R1016G是一种与功能增强效应相关的新的SQTS相关变异。“一分为二试验”是一种新的激发操作，可高度准确地识别SQTS变异携带者。
