TY - JOUR
T1 - Epidemiological, 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.
PY - 2010
Y1 - 2010
N2 - BACKGROUND:: Considering that ~2% of Caucasian controls host rare, non-synonymous 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 investigation 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 3741 LQTS referral cases (mostly Caucasian) and 1437 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 17/3741 (0.45%) cases compared with 7/1437 controls (0.49%, p=0.82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 in KCNQ1, 3 in KCNH2, and 2 in 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. CONCLUSIONS:: There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in about 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 pro-arrhythmic 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 ~2% of Caucasian controls host rare, non-synonymous 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 investigation 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 3741 LQTS referral cases (mostly Caucasian) and 1437 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 17/3741 (0.45%) cases compared with 7/1437 controls (0.49%, p=0.82). Among the 17 A572D-positive LQTS referrals, 10 (59%) hosted definite LQTS-causing mutations elsewhere (5 in KCNQ1, 3 in KCNH2, and 2 in 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. CONCLUSIONS:: There is sufficient evidence to conclude that A572D-SCN5A is not an independent, LQT3-causative mutation. A572D is present in about 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 pro-arrhythmic 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
U2 - https://doi.org/10.1016/j.hrthm.2010.04.014
DO - https://doi.org/10.1016/j.hrthm.2010.04.014
M3 - Article
C2 - 20403459
SN - 1547-5271
VL - 7
SP - 912
EP - 919
JO - Heart Rhythm
JF - Heart Rhythm
IS - 7
ER -