KCNE3 encodes an auxiliary beta subunit (potassium voltage-gated channel subfamily E regulatory subunit 3) that interacts with the alpha subunits of voltage-gated potassium channels by modulating gating kinetics and enhancing stability. KCNE3 expression is observed in several human tissue types, including cardiac tissue (Lundquist et al., 15698834). KCNE3 was originally classified as “disputed” for Brugada syndrome by the ClinGen Brugada Syndrome Gene Curation Expert Panel in 2017.
Contemporary data demonstrate that all key published variants now have population frequencies too high to be considered autosomal dominant causes of Brugada syndrome. KCNE3 was first reported in relation to Brugada syndrome in 2008 by Delpón et al., who identified a missense variant (c.296G>A, p.Arg99His) in a 36 year old male proband with Brugada syndrome (PMID: 19122847). This variant was also identified in a 45 year old male with Brugada syndrome by Jeong et al., 2024. Nakajima et al. identified missense variant (c.10A>G, p.Thr4Ala) in a 55 year old male proband with Brugada syndrome (PMID: 22987075). The same variant was reported in a single proband in a retrospective review of 71 sudden death cases, although this proband was also found to carry a KCNE3 variant (Oshima et al. PMID: 28747690). Campuzano et al. identified a missense variant (c.248G>A, p.Arg83His) in a SIDS case with negative autopsy results (PMID: 25016126).
Although the focus of this curation is the asserted relationship between KCNE3 and Brugada syndrome, additional publications suggesting a relationship between KCNE3 variants and hypertrophic cardiomyopathy, long QT syndrome, and atrial fibrillation were identified and briefly reviewed (PMID: 21967835, PMID: 19306396, PMID: 18209471, PMID: 16313760). The variants identified in these publications were determined to have population frequencies too high to be considered monogenic causes for the associated conditions.
KCNE3 and its association with Brugada syndrome was evaluated by the Hereditary Cardiovascular GCEP on July 22, 2025. Since its original curation in 2017, there has been no additional convincing evidence published to support this relationship. The classification of KCNE3 and Brugada syndrome remains disputed.
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