Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome

Background: 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 (SCD) remains unknown. Objective: To investigate the prevalence of potential disease-causing variants using gene panels including SLC4A3. Methods: In this multicenter study, genetic testing were performed in 34 index patients with SQTS. Pathogenicity of novel SLC4A3 variants were validated in a zebrafish embryo heart model. Results: Potentially disease-causing variants were identified in 26% of patients and were mainly (15%) located in SLC4A3: four patients heterozygous for novel non-synonymous SLC4A3 variants (p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His) and one patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2x in KCNQ1, and 1x in KCNJ2, and CACNA1C each). SLC4A3 variant-carriers (n=5) had similar heart rate but shorter QT and Jp-Tp intervals than non-carriers (n=29). Knockdown of slc4a3 in zebrafish resulted in shortened QTc intervals that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutant AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, nor p.Arg952His suggesting pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes. Conclusion: In around one-fourth of SQTS patients a potentially disease-causing variant can be identified. Non-synonymous variants in SLC4A3 represent most common cause of SQTS, underscoring the importance of including SLC4A3 in the genetic screening of patients with SQTS or SCD.