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A KCNQ1 Mutation Causes a High Penetrance for Familial Atrial Fibrillation


  • This work was supported by the American Heart Association predoctoral award PRE7370003 (DCB) and the National Heart Lung and Blood Institute grant R01 HL087039 (BPD).

  • M.J. Ackerman is a consultant for Biotronik, Boston Scientific, Medtronic, St. Jude Medical, and Transgenomic. In addition, there is a license agreement held between Transgenomic and Mayo Clinic Health Solutions and royalties are distributed in accordance with Mayo Clinic policy. E.R. Behr receives research funds from Biotronik, Boston-Scientific, St. Jude Medical, and the international SAEC. Other authors: No disclosures.

Address for correspondence: Brian P. Delisle, 800 Rose St. MS508, Lexington, KY 40536, USA. Fax: +859-323-1070; E-mail:

R231H Causes a High Penetrance for Familial AF


Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is expected to grow. A genetic predisposition for AF has long been recognized, but its manifestation in these patients likely involves a combination of rare and common genetic variants. Identifying genetic variants that associate with a high penetrance for AF would represent a significant breakthrough for understanding the mechanisms that associate with disease.

Method and Results

Candidate gene sequencing in 5 unrelated families with familial AF identified the KCNQ1 missense mutation p.Arg231His (R231H). In addition to AF, several of the family members have abnormal QTc intervals, syncope or experienced sudden cardiac arrest or death. KCNQ1 encodes the voltage-gated K+ channel that conducts the slowly activating delayed rectifier K+ current in the heart. Functional and computational analyses suggested that R231H increases KCNQ1 current (IKCNQ1) to shorten the atrial action potential (AP) duration. R231H is predicted to minimally affect ventricular excitability, but it prevented the increase in IKCNQ1 following PKA activation. The unique properties of R231H appeared to be caused by a loss in voltage-dependent gating.


The R231H variant causes a high penetrance for interfamilial early-onset AF. Our study indicates R231H likely shortens atrial refractoriness to promote a substrate for reentry. Additionally, R231H might cause abnormal ventricular repolarization by disrupting PKA activation of IKCNQ1. We conclude genetic variants, which increase IKs during the atrial AP, decrease the atrial AP duration, and/or shorten atrial refractoriness, present a high risk for interfamilial AF.