A Gain-of -Function SLC4A3 Mutation Causes Short-QT Syndrome: From Molecular Analysis to Novel Diagnostic Testing

Background: 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. Objectives: The aim of this study was to describe a new variant in the SQTS-associated gene SLC4A3 at the molecular and clinical levels. Methods: 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. Results: 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). Conclusions: 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.