KCNE5 – Brugada syndrome

Brugada syndrome is an inherited arrhythmia characterized by ST‐segment elevation and predisposition to ventricular fibrillation. KCNE5 (KCNE1L) encodes an X‐linked ancillary β‐subunit that modulates the cardiac transient outward K⁺ current (Ito) (Gene Symbol, Disease Name).

In a cohort of 205 Japanese Brugada syndrome or idiopathic ventricular fibrillation patients negative for SCN5A mutations, screening of KCNE5 identified two novel variants in four unrelated probands: c.241T>C (p.Tyr81His) in three individuals and c.276C>G (p.Asp92Glu) in one male proband, all hemizygous for these X‐linked alleles (4 probands) (PMID:21493962). No formal segregation beyond probands was reported.

KCNE5 variants were associated with a gain-of-function effect on Ito when coexpressed with Kv4.3 in vitro, showing increased current density and altered “notch‐and‐dome” action potential morphology compared to wild type (PMID:21493962).

In Kcne5 knockout mice, deletion led to increased ventricular KV currents, higher rates of premature beats and inducible polymorphic ventricular tachycardia, and shortened refractory periods, recapitulating key arrhythmic features of human Brugada syndrome (PMID:30289750).

Together, genetic and functional data support a pathogenic role for X‐linked KCNE5 gain-of-function variants in Brugada syndrome. Screening of KCNE5 should be considered in male patients with Brugada ECG manifestations and unexplained ventricular fibrillation.

Key take-home: Hemizygous KCNE5 variants confer gain-of-function of Ito and underlie Brugada syndrome in male patients, supporting incorporation of KCNE5 into diagnostic testing panels.

References

• Circulation. Arrhythmia and electrophysiology • 2011 • KCNE5 (KCNE1L) variants are novel modulators of Brugada syndrome and idiopathic ventricular fibrillation. PMID:21493962
• FASEB journal • 2019 • Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia. PMID:30289750

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