Vladimir Matchkov

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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 SLC4A3as a cause of SQTS or sudden cardiac death remains unknown.

OBJECTIVE: The purpose of this study was to investigate the prevalence of potential disease-causing variants using gene panels including SLC4A3.

METHODS: In this multicenter study, genetic testing was performed in 34 index patients with SQTS. The pathogenicity of novel SLC4A3variants was 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: 4 patients heterozygous for novel nonsynonymous SLC4A3 variants-p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His-and 1 patient with the known p.Arg370His variant. In other SQTS genes, potentially disease-causing variants were less frequent (2× in KCNQ1, 1× in KCNJ2, and CACNA1C each). SLC4A3 variant carriers (n = 5) had a similar heart rate but shorter QT and J point to T wave peak intervals than did noncarriers (n = 29). Knockdown of slc4a3 in zebrafish resulted in shortened heart rate-corrected QT intervals (calculated using the Bazett interval) 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 by p.Arg952His, suggesting the pathogenicity of these variants. Dysfunction in slc4a3/AE3 was associated with alkaline cytosol and shortened action potential of cardiomyocytes.

CONCLUSION: In about a quarter of patients with SQTS, a potentially disease-causing variant can be identified. Nonsynonymous variants in SLC4A3 represent the most common cause of SQTS, underscoring the importance of including SLC4A3in the genetic screening of patients with SQTS or sudden cardiac death.

Original languageEnglish
JournalHeart Rhythm
Publication statusE-pub ahead of print - 15 Feb 2023

Bibliographical note

Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

See relations at Aarhus University Citationformats

ID: 312380704