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

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 Henrik K
Heart Rhythm. 2023;[Epub] doi:10.1016/j.hrthm.2023.02.010
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.
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