TY - JOUR
T1 - Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation
AU - Tester, David J.
AU - Valdivia, Carmen
AU - Harris-Kerr, Carole
AU - Alders, Marielle
AU - Salisbury, Benjamin A.
AU - Wilde, Arthur A.M.
AU - Makielski, Jonathan C.
AU - Ackerman, Michael J.
N1 - Funding Information:
The analyses were performed in Dr. Ackerman's research program with support from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program . Dr. Wilde's research program is supported by Interuniversity Cardiology Institute the Netherlands (ICIN) project 27 and a Leducq programm grant “ Alliance against sudden cardiac death .” Dr. Carole Harris-Kerr and Dr. Benjamin A. Salisbury are employees of PGxHealth, which offers the FAMILION LQTS Test, and are stockholders of the parent company, Clinical Data. Dr. Wilde is on PGxHealth's Scientific Advisory Board. Dr. Ackerman is a consultant for PGxHealth and chairs their FAMILION Medical/Scientific Advisory Board (approved by Mayo Clinic's Medical-Industry Relations Office and Conflict of Interests Review Board). “Cardiac channel gene screen” and “know-how relating to long QT genetic testing” license agreements, resulting in consideration and royalty payments, were established between Genaissance Pharmaceuticals (now PGxHealth) and Mayo Medical Ventures (now Mayo Clinic Health Solutions) in 2004.
PY - 2010/7
Y1 - 2010/7
N2 - 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.
AB - 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.
KW - Genetic testing
KW - Long QT syndrome
KW - Mutation
KW - SCN5A
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U2 - 10.1016/j.hrthm.2010.04.014
DO - 10.1016/j.hrthm.2010.04.014
M3 - Article
C2 - 20403459
AN - SCOPUS:77953837444
VL - 7
SP - 912
EP - 919
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
IS - 7
ER -