BACKGROUND: Considering that approximately 2% of Caucasian controls host rare, nonsynonymous variants in the SCN5A-encoded cardiac sodium channel, caution must be exercised when interpreting SCN5A genetic test results for long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to determine if A572D-SCN5A is a pathogenic mutation, a possible functional modifier, or background "genetic noise." METHODS: The frequency of A572D was compared between 3,741 LQTS referral cases (mostly Caucasian) and 1,437 Caucasian controls. A572D-SCN5A was engineered into SCN5A using the most commonly spliced transcript (Q1077del, hH1c clone) in the setting of either H558 or R558 for heterologous expression/patch clamp studies in HEK293 cells. RESULTS: A572D-SCN5A was detected in 17 (0.45%) of 3,741 cases compared with 7 (0.49%) of 1,437 controls (P = .82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 KCNQ1, 3 KCNH2, 2 SCN5A). Functional studies showed no gating kinetic or current density differences compared with wild-type channels in the context of H558 but showed moderate dysfunction when expressed in H558R-SCN5A, with which it is invariably associated. CONCLUSION: There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in approximately 0.5% of both cases and controls and has a wild-type phenotype when expressed in HEK293 cells. However, in the context of H558R-SCN5A, persistent late sodium current emerges, indicating that A572D/H558R could be a proarrhythmic factor akin to S1103Y. These findings underscore the scrutiny necessary to distinguish truly pathogenic mutations from functional polymorphisms and otherwise innocuous, rare genetic variants in SCN5A. These results also question how much cellular dysfunction for a mutation is required in vitro to support pathogenicity. Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
BACKGROUND: Considering that approximately 2% of Caucasian controls host rare, nonsynonymous variants in the SCN5A-encoded cardiac sodium channel, caution must be exercised when interpreting SCN5A genetic test results for long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to determine if A572D-SCN5A is a pathogenic mutation, a possible functional modifier, or background "genetic noise." METHODS: The frequency of A572D was compared between 3,741 LQTS referral cases (mostly Caucasian) and 1,437 Caucasian controls. A572D-SCN5A was engineered into SCN5A using the most commonly spliced transcript (Q1077del, hH1c clone) in the setting of either H558 or R558 for heterologous expression/patch clamp studies in HEK293 cells. RESULTS:A572D-SCN5A was detected in 17 (0.45%) of 3,741 cases compared with 7 (0.49%) of 1,437 controls (P = .82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 KCNQ1, 3 KCNH2, 2 SCN5A). Functional studies showed no gating kinetic or current density differences compared with wild-type channels in the context of H558 but showed moderate dysfunction when expressed in H558R-SCN5A, with which it is invariably associated. CONCLUSION: There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in approximately 0.5% of both cases and controls and has a wild-type phenotype when expressed in HEK293 cells. However, in the context of H558R-SCN5A, persistent late sodium current emerges, indicating that A572D/H558R could be a proarrhythmic factor akin to S1103Y. These findings underscore the scrutiny necessary to distinguish truly pathogenic mutations from functional polymorphisms and otherwise innocuous, rare genetic variants in SCN5A. These results also question how much cellular dysfunction for a mutation is required in vitro to support pathogenicity. Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Authors: Wojciech Zareba; Arthur J Moss; Emanuela H Locati; Michael H Lehmann; Derick R Peterson; W Jackson Hall; Peter J Schwartz; G Michael Vincent; Silvia G Priori; Jesaia Benhorin; Jeffrey A Towbin; Jennifer L Robinson; Mark L Andrews; Carlo Napolitano; Katherine Timothy; Li Zhang; Aharon Medina Journal: J Am Coll Cardiol Date: 2003-07-02 Impact factor: 24.094
Authors: Jonathan C Makielski; Bin Ye; Carmen R Valdivia; Matthew D Pagel; Jielin Pu; David J Tester; Michael J Ackerman Journal: Circ Res Date: 2003-09-18 Impact factor: 17.367
Authors: Suraj Kapa; David J Tester; Benjamin A Salisbury; Carole Harris-Kerr; Manish S Pungliya; Marielle Alders; Arthur A M Wilde; Michael J Ackerman Journal: Circulation Date: 2009-10-19 Impact factor: 29.690
Authors: Kazuo Ueda; Carmen Valdivia; Argelia Medeiros-Domingo; David J Tester; Matteo Vatta; Gianrico Farrugia; Michael J Ackerman; Jonathan C Makielski Journal: Proc Natl Acad Sci U S A Date: 2008-06-30 Impact factor: 11.205
Authors: A Marjamaa; C Newton-Cheh; K Porthan; A Reunanen; P Lahermo; H Väänänen; A Jula; H Karanko; H Swan; L Toivonen; M S Nieminen; M Viitasalo; L Peltonen; L Oikarinen; A Palotie; K Kontula; V Salomaa Journal: J Intern Med Date: 2009-10-25 Impact factor: 8.989
Authors: Beatriz Ortiz-Bonnin; Susanne Rinné; Robin Moss; Anne K Streit; Michael Scharf; Katrin Richter; Anika Stöber; Arne Pfeufer; Gunnar Seemann; Stefan Kääb; Britt-Maria Beckmann; Niels Decher Journal: Pflugers Arch Date: 2016-06-11 Impact factor: 3.657
Authors: Tina Jenewein; Thomas Neumann; Damir Erkapic; Malte Kuniss; Marcel A Verhoff; Gerhard Thiel; Silke Kauferstein Journal: Int J Legal Med Date: 2017-12-06 Impact factor: 2.686
Authors: Olha M Koval; Jedidiah S Snyder; Roseanne M Wolf; Ryan E Pavlovicz; Patric Glynn; Jerry Curran; Nicholas D Leymaster; Wen Dun; Patrick J Wright; Natalia Cardona; Lan Qian; Colleen C Mitchell; Penelope A Boyden; Philip F Binkley; Chenglong Li; Mark E Anderson; Peter J Mohler; Thomas J Hund Journal: Circulation Date: 2012-09-24 Impact factor: 29.690
Authors: Lena Refsgaard; Anders G Holst; Golnaz Sadjadieh; Stig Haunsø; Jonas B Nielsen; Morten S Olesen Journal: Eur J Hum Genet Date: 2012-02-29 Impact factor: 4.246