Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome
Heart rhythm(2023)
摘要
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 prev-alence 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 SLC4A3-variants 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 in-tervals (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 patho-genicity of these variants. Dysfunction in slc4a3/AE3 was associ-ated 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. Nonsy-nonymous 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 sud-den cardiac death.
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