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

David J. Tester, Carmen Valdivia, Carole Harris-Kerr, Marielle Alders, Benjamin A. Salisbury, Arthur A M Wilde, Jonathan C. Makielski, Michael John Ackerman

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)912-919
Number of pages8
JournalHeart Rhythm
Volume7
Issue number7
DOIs
StatePublished - Jul 2010

Fingerprint

Long QT Syndrome
Mutation
HEK293 Cells
Referral and Consultation
Sodium Channels
Virulence
Noise
Clone Cells
Sodium
Phenotype

Keywords

  • Genetic testing
  • Long QT syndrome
  • Mutation
  • SCN5A

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation. / Tester, David J.; Valdivia, Carmen; Harris-Kerr, Carole; Alders, Marielle; Salisbury, Benjamin A.; Wilde, Arthur A M; Makielski, Jonathan C.; Ackerman, Michael John.

In: Heart Rhythm, Vol. 7, No. 7, 07.2010, p. 912-919.

Research output: Contribution to journalArticle

Tester, David J. ; Valdivia, Carmen ; Harris-Kerr, Carole ; Alders, Marielle ; Salisbury, Benjamin A. ; Wilde, Arthur A M ; Makielski, Jonathan C. ; Ackerman, Michael John. / Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation. In: Heart Rhythm. 2010 ; Vol. 7, No. 7. pp. 912-919.
@article{605e4dac6e7547cd99d7404479563b8e,
title = "Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation",
abstract = "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.",
keywords = "Genetic testing, Long QT syndrome, Mutation, SCN5A",
author = "Tester, {David J.} and Carmen Valdivia and Carole Harris-Kerr and Marielle Alders and Salisbury, {Benjamin A.} and Wilde, {Arthur A M} and Makielski, {Jonathan C.} and Ackerman, {Michael John}",
year = "2010",
month = "7",
doi = "10.1016/j.hrthm.2010.04.014",
language = "English (US)",
volume = "7",
pages = "912--919",
journal = "Heart Rhythm",
issn = "1547-5271",
publisher = "Elsevier",
number = "7",

}

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 John

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

UR - http://www.scopus.com/inward/record.url?scp=77953837444&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953837444&partnerID=8YFLogxK

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 -