TY - JOUR
T1 - Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome
AU - Christiansen, Morten Krogh
AU - Kjær-Sørensen, Kasper
AU - Clavsen, Natacha C
AU - Dittmann, Sven
AU - Jensen, Maja Fuhlendorff
AU - Guldbrandsen, Halvor Østerby
AU - Pedersen, Lisbeth Nørum
AU - Sørensen, Rikke Hasle
AU - Lildballe, Dorte Launholt
AU - Müller, Klara
AU - Müller, Patrick
AU - Vogel, Kira
AU - Rudic, Boris
AU - Borggrefe, Martin
AU - Oxvig, Claus
AU - Aalkjær, Christian
AU - Schulze-Bahr, Eric
AU - Matchkov, Vladimir
AU - Bundgaard, Henning
AU - Jensen, Henrik Kjærulf
N1 - Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
PY - 2023/8
Y1 - 2023/8
N2 - 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 remains unknown.OBJECTIVE: The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients 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 9 (26%) 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 formula) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting 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 SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death.
AB - 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 remains unknown.OBJECTIVE: The purpose of this study was to investigate the prevalence of potential disease-causing variants in SQTS patients 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 9 (26%) 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 formula) that could be rescued by overexpression of the native human SLC4A3-encoded protein (AE3), but neither by the mutated AE3 variants p.Arg600Cys, p.Arg621Trp, p.Glu852Asp nor by p.Arg952His, suggesting 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 SLC4A3 in the genetic screening of patients with SQTS or sudden cardiac death.
KW - Animals
KW - Arrhythmias, Cardiac
KW - Death, Sudden, Cardiac/prevention & control
KW - Electrocardiography/methods
KW - Humans
KW - Zebrafish
KW - QT interval
KW - Short QT syndrome
KW - Genetic testing
KW - Mutation
KW - SLC4A3
KW - Heart model
UR - http://www.scopus.com/inward/record.url?scp=85150267507&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2023.02.010
DO - 10.1016/j.hrthm.2023.02.010
M3 - Journal article
C2 - 36806574
SN - 1547-5271
VL - 20
SP - 1136
EP - 1143
JO - Heart Rhythm
JF - Heart Rhythm
IS - 8
ER -