Enhancing the Predictive Power of Mutations in the C-Terminus of the KCNQ1-Encoded Kv7.1 Voltage-Gated Potassium Channel

  • Jamie D. Kapplinger
  • Andrew S. Tseng
  • Benjamin A. Salisbury
  • David J. Tester
  • Thomas E. Callis
  • Marielle Alders
  • Arthur A. M. Wilde
  • Michael J. AckermanEmail author


Despite the overrepresentation of Kv7.1 mutations among patients with a robust diagnosis of long QT syndrome (LQTS), a background rate of innocuous Kv7.1 missense variants observed in healthy controls creates ambiguity in the interpretation of LQTS genetic test results. A recent study showed that the probability of pathogenicity for rare missense mutations depends in part on the topological location of the variant in Kv7.1’s various structure-function domains. Since the Kv7.1’s C-terminus accounts for nearly 50 % of the overall protein and nearly 50 % of the overall background rate of rare variants falls within the C-terminus, further enhancement in mutation calling may provide guidance in distinguishing pathogenic long QT syndrome type 1 (LQT1)-causing mutations from rare non-disease-causing variants in the Kv7.1’s C-terminus. Therefore, we have used conservation analysis and a large case-control study to generate topology-based estimative predictive values to aid in interpretation, identifying three regions of high conservation within the Kv7.1’s C-terminus which have a high probability of LQT1 pathogenicity.


Conservation analysis Estimated predictive value KCNQ1 (Kv7.1) Long QT syndrome 



J.D.K. is supported by the NIH grant GM72474-08 and thanks the Mayo Clinic MSTP for fostering an outstanding environment for physician-scientist training. This project was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (M.J.A.). We acknowledge the support from the Netherlands CardioVascular Research Initiative (CVON-PREDICT project): the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (A.A.M.W.).


T.E.C. is an employee of Transgenomic Inc. B.A.S. is an employee of Knome, Inc. M.J.A. is a consultant for Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical, Inc., and Transgenomic. Intellectual property derived from M.J.A.’s research program resulted in license agreements in 2004 between Mayo Clinic Ventures (formerly Mayo Medical Ventures) and Genaissance Pharmaceuticals (now Transgenomic) with respect to their FAMILION-LQTS and FAMILION-CPVT genetic tests.

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jamie D. Kapplinger
    • 1
    • 2
    • 3
  • Andrew S. Tseng
    • 1
  • Benjamin A. Salisbury
    • 4
  • David J. Tester
    • 2
    • 3
    • 5
  • Thomas E. Callis
    • 6
  • Marielle Alders
    • 7
  • Arthur A. M. Wilde
    • 8
    • 9
  • Michael J. Ackerman
    • 1
    • 2
    • 3
    • 5
    • 10
    Email author
  1. 1.Mayo Medical SchoolMayo ClinicRochesterUSA
  2. 2.Department of Molecular Pharmacology and Experimental TherapeuticsMayo ClinicRochesterUSA
  3. 3.Windland Smith Rice Sudden Death Genomics LaboratoryMayo ClinicRochesterUSA
  4. 4.Knome, Inc.CambridgeUSA
  5. 5.Department of Medicine, Division of Cardiovascular DiseasesMayo ClinicRochesterUSA
  6. 6.Transgenomic Inc.New HavenUSA
  7. 7.Department of Clinical Genetics, Academic Medical CenterUniversity of AmsterdamAmsterdamNetherlands
  8. 8.Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical CenterUniversity of AmsterdamAmsterdamNetherlands
  9. 9.Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary DisordersJeddahKingdom of Saudi Arabia
  10. 10.Department of Pediatrics, Division of Pediatric CardiologyMayo ClinicRochesterUSA

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