Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome.
Short QT syndrome (SQTS) is a rare inherited cardiac disease associated with a high risk of ventricular and atrial arrhythmias and sudden cardiac death. The disease often runs in families, but a disease-causing genetic variant is identified in only ±20% of index patients. This indicates that yet undetected causal genetic variants exist. SQTS is considered a purely electric Heart disease caused by genetic anomalies in charged molecule transporters (ions as potassium, calcium..). Indeed, the heart pump is electrically controlled and default in the electric flow in cardiac cells may cause malfunction or even stop the pump leading to death.
A new gene potentially associated with short QT syndrome has been identified (i.e. the so-called SLC4A3 anion exchanger gene ) and is associated with another molecule (chloride/ bicardbonate) involved the proper functioning of eleclric current in cardiac cells (cardiomyocyte).
Since the discovery of the SLC4A3 gene as a cause of SQTS, genome-wide association studies have further linked SLC4A3 to QT interval length as well as QT dynamics in response to exercise. However, to date the prevalence of pathogenic variants in SLC4A3 has not been reported and therefore the clinical importance of SLC4A3 variants as a cause of SQTS or SCD has remained unknown.
To address this, we investigated the prevalence of potential disease-causing variants using gene panels including SLC4A3 in a uniquely large German-Danish cohort of unrelated patients with SQTS and further investigated potentially disease-causing SLC4A3 variants in a zebrafish embryo heart model.
Potentially disease-causing variants were identified in 9 (26%) patients and were mainly (15%) located in the SLC4A3 gene: 5 patients had different variants in the SLC4A3 gene. In other SQTS genes, potentially disease-causing variants were less frequent (two in KCNQ1, one in KCNJ2, and CACNA1C each). The five SLC4A3 variant carriers had a similar heart rate but shorter QT interval than the 29 non-carriers. Experimental studies of the new SLC4A3 genetic variants in our zebrafish embryo heart model resulted in shortened heart rate–corrected QT intervals and dysfunction of the SLC4A3 anion exchanger suggesting the pathogenicity of these variants.
Conclusions: We identified SCL4A3 as a major cause of SQTS and further established an experimental zebrafish AE3 embryo heart model for SQTS in which the novel SLC4A3 variants showed a lack to normalize shortened QT interval. This takes the total proportion of patients with an identified genetic cause of SQTS to about a quarter and establishes SLC4A3 as the most common cause of SQTS to date. Thus, our findings highlight the importance of other than cation channel–driven mechanisms in SQTS and underscore the importance of including SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death.
Christiansen MK, Kjær-Sørensen K, Clavsen NC, Dittmann S, Jensen MF, Guldbrandsen HØ, Pedersen LN, Sørensen RH, Lildballe DL, Müller K, Müller P, Vogel K, Rudic B, Borggrefe M, Oxvig C, Aalkjær C, Schulze-Bahr E, Matchkov V, Bundgaard H, Jensen HK. Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome.
Heart Rhythm. 2023 Aug;20(8):1136-1143. doi: 10.1016/j.hrthm.2023.02.010. Epub 2023 Feb 15. PMID: 36806574
Prepared by Hendrik Jensen and Sophie Pierre