Mutations in Conserved Amino Acids in the KCNQ1 Channel and Risk of Cardiac Events in Type-1 Long-QT Syndrome


  • This work was supported in part by research grant HL-33843 and HL-51618 from the National Institutes of Health, Bethesda, MD; an unrestricted grant from BioReference Laboratory, Inc., Elmwood Park, NJ; and by the Dutch Heart Foundation 2000.059 and Foundation Leducq Transatlantic network of excellence grant (05 CVD01, preventing sudden death).

  • This research was carried out while Dr. Christian Jons was a Mirowski-Moss Career Development Awardee at the University of Rochester Medical Center, Rochester, NY.

  • Dr. Qi is a participant on ZJST 2006 Qianjiang Tellant Grant, Department of Science & Technology, Zhejiang Province, China. Dr. Shimizu is Principal Investigator on a health sciences research grant (H-18-Research on Human Genome-002) from the Ministry of Health, Labour and Welfare, Japan. Dr. Lopes reports a patent application relevant to this topic. Dr. Ackerman is a paid consultant for clinical data (formerly Genaissance Pharmaceuticals) with respect to the FAMILION genetic test for cardiac ion channel mutations.

Address for correspondence: Christian Jons, M.D., Box 653, The Heart Research Follow-Up Program, University of Rochester Medical Center, Elmwood Ave., Rochester, NY 14607, USA. Fax: 585-273-5283; E-mail:


Background: Type-1 long-QT syndrome (LQT1) is caused by mutations in the KCNQ1 gene. The purpose of this study was to investigate whether KCNQ1 mutations in highly conserved amino acid residues within the voltage-gated potassium channel family are associated with an increased risk of cardiac events.

Methods and Results: The study population involved 492 LQT1 patients with 54 missense mutations in the transmembrane region of the KCNQ1 channel. The amino acid sequences of the transmembrane region of 38 human voltage-gated potassium channels were aligned. An adjusted Shannon entropy score for each amino acid residue was calculated ranging from 0 (no conservation) to 1.0 (full conservation). Cox analysis was used to identify independent factors associated with the first cardiac event (syncope, aborted cardiac arrest, or death). Patients were subcategorized into tertiles by their adjusted Shannon entropy scores. The lowest tertile (score 0–0.469; n = 146) was used as a reference group; patients with intermediate tertile scores (0.470–0.665; n = 150) had no increased risk of cardiac events (HR = 1.19, P = 0.42) or aborted cardiac arrest/sudden cardiac death (HR = 1.58, P = 0.26), and those with the highest tertile scores (>0.665; n = 196) showed significantly increased risk of cardiac events (HR = 3.32, P <0.001) and aborted cardiac arrest/sudden cardiac death (HR = 2.62, P = 0.04). The increased risk in patients with the highest conservation scores was independent of QTc, gender, age, and beta-blocker therapy.

Conclusions: Mutations in highly conserved amino acid residues in the KCNQ1 gene are associated with a significant risk of cardiac events independent of QTc, gender, and beta-blocker therapy.