Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation.
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.


CONCLUSIONS
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.
Tester
David J
DJ
Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Valdivia
Carmen
C
Harris-Kerr
Carole
C
Alders
Marielle
M
Salisbury
Benjamin A
BA
Wilde
Arthur A M
AA
Makielski
Jonathan C
JC
Ackerman
Michael J
MJ
D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011110:Polymorphism, Genetic / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics*; D044465:White People / Q000235:genetics
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels
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