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

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• 作者：Jamie D. Kapplinger ; Andrew S. Tseng…
• 关键词：Conservation analysis ; Estimated predictive value ; KCNQ1 (Kv7.1) ; Long QT syndrome
• 刊名：Journal of Cardiovascular Translational Research
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：8
• 期：3
• 页码：187-197
• 全文大小：931 KB
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• 作者单位：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) (10) (2) (3) (5)
  
  1. Mayo Medical School, Mayo Clinic, Rochester, MN, USA
  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
  3. Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA
  4. Knome, Inc., Cambridge, MA, USA
  5. Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
  6. Transgenomic Inc., New Haven, CT, USA
  7. Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  8. Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  9. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia
  10. Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA
  
• 刊物主题：Cardiology; Human Genetics; Biomedical Engineering; Biomedicine general; Medicine/Public Health, general;
• 出版者：Springer US
• ISSN：1937-5395

文摘

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.