SLC4A3 – Short QT syndrome

Short QT syndrome (SQTS) is an autosomal dominantly inherited channelopathy characterized by pathologically abbreviated QT intervals, syncope, ventricular fibrillation, and sudden cardiac death. Although six cation channel genes account for fewer than 25% of SQTS cases, the anion exchanger gene SLC4A3 has emerged as a novel SQTS susceptibility gene. SLC4A3 encodes the cardiac chloride–bicarbonate exchanger AE3, and pathogenic variants result in loss of AE3 surface expression and reduced bicarbonate transport, implicating altered anion homeostasis in myocardial repolarization.

In a 2017 Nature Communications report, two unrelated SQTS families were shown to carry the heterozygous missense variant c.1028G>A (p.Arg343His) in SLC4A3, which co-segregated with disease across affected relatives (PMID:29167417). Biochemical assays demonstrated markedly reduced membrane localization and diminished bicarbonate flux of mutant AE3 compared to wild type. Carriers experienced recurrent syncope, ventricular fibrillation, and documented short QTc intervals. No other pathogenic variants were detected in established SQTS genes in these pedigrees, and the variant was absent from large population databases.

A multicenter Heart Rhythm cohort of 34 index patients identified SLC4A3 variants in 5 individuals (15%), including the recurrent p.Arg370His and novel changes p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His (PMID:36806574). These SLC4A3 variants represented the most frequent genetic finding in the series, exceeding variant detection rates in KCNQ1, KCNJ2, and CACNA1C. Heterozygous carriers exhibited significantly shorter QT and J–Tpeak intervals than noncarriers. All identified variants were rare, predicted deleterious missense changes, supporting a dominant-negative or haploinsufficient mechanism.

Inheritance of SQTS due to SLC4A3 follows an autosomal dominant mode without evidence for compound heterozygosity. Familial segregation in two kindreds confirmed multiple affected relatives with the c.1028G>A (p.Arg343His) allele (PMID:29167417). The absence of homozygous loss-of-function alleles in population cohorts suggests full penetrance of heterozygous variants. Genotype–phenotype correlations are consistent across families and sporadic cases, informing clinical risk assessment.

Functional validation in zebrafish embryo models has been pivotal in confirming pathogenicity. Morpholino-mediated slc4a3 knockdown induced elevated cardiac intracellular pH, shortened corrected QT intervals, and reduced systolic duration, mirroring human SQTS. Overexpression of wild-type human AE3 rescued these phenotypes, whereas AE3 variants p.Arg343His, p.Arg600Cys, p.Arg621Trp, p.Glu852Asp, and p.Arg952His failed to restore normal electrophysiology (PMID:29167417, PMID:36806574). These data confirm that impaired anion exchange alters myocardial repolarization via increased pHi and reduced intracellular Cl⁻.

An evidence-based reappraisal by the ClinGen Channelopathy Expert Panel classified SLC4A3 as having strong to moderate evidence for SQTS causation, endorsing its inclusion in diagnostic panels (PMID:34557911). The integration of segregation data, cohort prevalence, variant spectrum, and robust zebrafish rescue experiments establishes SLC4A3-associated SQTS as a clinically actionable, autosomal dominant channelopathy. Key Take-home: Heterozygous SLC4A3 variants are a validated cause of Short QT syndrome and should be included in genetic testing for arrhythmia risk stratification.

References

• Nature communications • 2017 • Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. PMID:29167417
• Heart rhythm • 2023 • Genetic analysis identifies the SLC4A3 anion exchanger as a major gene for short QT syndrome. PMID:36806574
• European heart journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911

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