KCNE3 – Brugada Syndrome

Brugada syndrome (BrS) associated with KCNE3 follows an autosomal dominant inheritance pattern. Two unrelated probands have been reported harboring rare KCNE3 missense variants: c.10A>G (p.Thr4Ala) in a Japanese patient with syncope (PMID:22987075) and c.296G>A (p.Arg99His) in a separate BrS case (PMID:19122847). In one family carrying the p.Arg99His variant, all 4 phenotype-positive members carried the variant and none of 3 unaffected relatives did, supporting segregation (PMID:19122847).

Functional studies of both p.Thr4Ala and p.Arg99His variants demonstrate a marked gain-of-function of the transient outward potassium current (Ito) in heterologous expression systems, concordant with the BrS electrophysiological substrate (PMID:22987075; PMID:19122847).

Key take-home: KCNE3 missense variants may contribute to BrS risk through Ito gain-of-function, but current genetic evidence is limited; KCNE3 sequencing may be considered in genotype-negative BrS cases.

References

• Circulation journal : official journal of the Japanese Circulation Society • 2012 • KCNE3 T4A as the genetic basis of Brugada-pattern electrocardiogram. PMID:22987075
• Circulation. Arrhythmia and electrophysiology • 2008 • Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. PMID:19122847

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