Brett M Kroncke1, Tao Yang1, Prince Kannankeril2, M Benjamin Shoemaker1, Dan M Roden3. 1. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 2. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. 3. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee. Electronic address: dan.roden@vanderbilt.edu.
Abstract
BACKGROUND: A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants. OBJECTIVE: The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation. METHODS: We used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels. RESULTS: The structural analysis indicates that KCNQ1 Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1 Val162Met is benign. CONCLUSION: Proximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.
BACKGROUND: A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants. OBJECTIVE: The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation. METHODS: We used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels. RESULTS: The structural analysis indicates that KCNQ1Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1Val162Met is benign. CONCLUSION: Proximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.
Authors: Ping Yang; Hideaki Kanki; Benoit Drolet; Tao Yang; Jian Wei; Prakash C Viswanathan; Stefan H Hohnloser; Wataru Shimizu; Peter J Schwartz; Marshall Stanton; Katherine T Murray; Kris Norris; Alfred L George; Dan M Roden Journal: Circulation Date: 2002-04-23 Impact factor: 29.690
Authors: Jamie D Kapplinger; David J Tester; Benjamin A Salisbury; Janet L Carr; Carole Harris-Kerr; Guido D Pollevick; Arthur A M Wilde; Michael J Ackerman Journal: Heart Rhythm Date: 2009-06-23 Impact factor: 6.343
Authors: Michael J Meyer; Ryan Lapcevic; Alfonso E Romero; Mark Yoon; Jishnu Das; Juan Felipe Beltrán; Matthew Mort; Peter D Stenson; David N Cooper; Alberto Paccanaro; Haiyuan Yu Journal: Hum Mutat Date: 2016-02-18 Impact factor: 4.878
Authors: Sarah S Kalia; Kathy Adelman; Sherri J Bale; Wendy K Chung; Christine Eng; James P Evans; Gail E Herman; Sophia B Hufnagel; Teri E Klein; Bruce R Korf; Kent D McKelvey; Kelly E Ormond; C Sue Richards; Christopher N Vlangos; Michael Watson; Christa L Martin; David T Miller Journal: Genet Med Date: 2016-11-17 Impact factor: 8.822
Authors: Monkol Lek; Konrad J Karczewski; Eric V Minikel; Kaitlin E Samocha; Eric Banks; Timothy Fennell; Anne H O'Donnell-Luria; James S Ware; Andrew J Hill; Beryl B Cummings; Taru Tukiainen; Daniel P Birnbaum; Jack A Kosmicki; Laramie E Duncan; Karol Estrada; Fengmei Zhao; James Zou; Emma Pierce-Hoffman; Joanne Berghout; David N Cooper; Nicole Deflaux; Mark DePristo; Ron Do; Jason Flannick; Menachem Fromer; Laura Gauthier; Jackie Goldstein; Namrata Gupta; Daniel Howrigan; Adam Kiezun; Mitja I Kurki; Ami Levy Moonshine; Pradeep Natarajan; Lorena Orozco; Gina M Peloso; Ryan Poplin; Manuel A Rivas; Valentin Ruano-Rubio; Samuel A Rose; Douglas M Ruderfer; Khalid Shakir; Peter D Stenson; Christine Stevens; Brett P Thomas; Grace Tiao; Maria T Tusie-Luna; Ben Weisburd; Hong-Hee Won; Dongmei Yu; David M Altshuler; Diego Ardissino; Michael Boehnke; John Danesh; Stacey Donnelly; Roberto Elosua; Jose C Florez; Stacey B Gabriel; Gad Getz; Stephen J Glatt; Christina M Hultman; Sekar Kathiresan; Markku Laakso; Steven McCarroll; Mark I McCarthy; Dermot McGovern; Ruth McPherson; Benjamin M Neale; Aarno Palotie; Shaun M Purcell; Danish Saleheen; Jeremiah M Scharf; Pamela Sklar; Patrick F Sullivan; Jaakko Tuomilehto; Ming T Tsuang; Hugh C Watkins; James G Wilson; Mark J Daly; Daniel G MacArthur Journal: Nature Date: 2016-08-18 Impact factor: 49.962
Authors: Corey L Anderson; Saba Munawar; Louise Reilly; Timothy J Kamp; Craig T January; Brian P Delisle; Lee L Eckhardt Journal: Front Cardiovasc Med Date: 2022-07-04
Authors: Peter M Kekenes-Huskey; Don E Burgess; Bin Sun; Daniel C Bartos; Ezekiel R Rozmus; Corey L Anderson; Craig T January; Lee L Eckhardt; Brian P Delisle Journal: Int J Mol Sci Date: 2022-07-02 Impact factor: 6.208