KCNE1 – Atrial Fibrillation

KCNE1 encodes the minK β-subunit of the cardiac I_Ks potassium channel, which modulates repolarization of atrial myocytes. Impaired I_Ks function or inappropriate gain of function can alter atrial action potential duration and promote atrial fibrillation (AF).

Two unrelated early-onset lone AF probands (T (p.Gly25Val) and c.179G>A (p.Gly60Asp) absent in 432 control alleles; one variant was inherited from an affected mother, providing segregation evidence (1 relative) (PMID:22471742). No KCNE1 coding mutations were detected in six Dutch AF families, underscoring locus heterogeneity (PMID:25696507).

Functional studies in heterologous systems demonstrated that both p.Gly25Val and p.Gly60Asp confer a marked gain of I_Ks current with faster activation and slowed deactivation, consistent with action potential shortening and AF predisposition (PMID:22471742).

Population analyses yield mixed findings. The common p.Asp85Asn variant showed no enrichment among AF cases in an electronic medical record cohort (PMID:25410959), whereas a meta-analysis of 14 case–control studies reported that the G38S polymorphism increases AF risk under multiple genetic models (PMID:28640127).

Overall, the clinical validity of KCNE1 for atrial fibrillation is Limited: only two unrelated probands, modest segregation, but concordant gain-of-function data. Genetic evidence is Limited due to small numbers of families; functional evidence is Moderate based on in vitro electrophysiology. Larger cohorts and additional familial segregation are required to move beyond a Limited classification.

Key Take-home: KCNE1 gain-of-function missense mutations can predispose to early-onset AF, supported by functional assays, but further genetic validation is needed before routine diagnostic screening.

References

• BMC medical genetics • 2012 • Mutations in the potassium channel subunit KCNE1 are associated with early-onset familial atrial fibrillation. PMID:22471742
• Netherlands heart journal • 2005 • Molecular genetic analysis of six Dutch families with atrial fibrillation. PMID:25696507
• Circulation. Cardiovascular genetics • 2015 • Examining rare and low-frequency genetic variants previously associated with lone or familial forms of atrial fibrillation in an electronic medical record system: a cautionary note. PMID:25410959
• Medicine • 2017 • Association between KCNE1 G38S gene polymorphism and risk of atrial fibrillation: A PRISMA-compliant meta-analysis. PMID:28640127

Evidence Based Scoring (AI generated)