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Further Insights in the Most Common SCN 5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect

View Article: PubMed Central - PubMed

ABSTRACT

Background: Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. SCN5A‐E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype–phenotype relationship in a large family carrying SCN5A‐E1784K and SCN5A‐H558R polymorphism.

Methods and results: Clinical work‐up, follow‐up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A‐E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A‐H558R did not significantly alter the phenotype of SCN5A‐E1784K carriers. Fourteen SCN5A‐E1784K patients underwent implantable cardioverter‐defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow‐up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A‐E1784K and SCN5A‐H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole‐cell patch‐clamp techniques. Co‐expression of SCN5A‐E1784K and SCN5A‐WT reduced INa,P to 70.03% of WT, shifted steady‐state inactivation by −11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A‐E1784K was co‐expressed with SCN5A‐H558R.

Conclusions: We demonstrate a strong genotype‐phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A‐E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.

No MeSH data available.


Related in: MedlinePlus

A, Receiver operating characteristic curve for PR interval, QRS duration, and QTc interval for the identification of SCN5A‐E1784K carriers vs noncarriers. The best correlation was found for QTc interval (area under the curve 0.993). B, Kaplan–Meier event‐free survival curves for SCN5A‐E1784K mutation carrier vs noncarriers are displayed. Noncarriers had no cardiac events. Four mutation carriers developed sudden cardiac arrest and ventricular fibrillation beyond the age of 40 years.
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jah31596-fig-0002: A, Receiver operating characteristic curve for PR interval, QRS duration, and QTc interval for the identification of SCN5A‐E1784K carriers vs noncarriers. The best correlation was found for QTc interval (area under the curve 0.993). B, Kaplan–Meier event‐free survival curves for SCN5A‐E1784K mutation carrier vs noncarriers are displayed. Noncarriers had no cardiac events. Four mutation carriers developed sudden cardiac arrest and ventricular fibrillation beyond the age of 40 years.

Mentions: In the receiver operating characteristic analysis, QRS interval was not found to be predictive for the identification of an SCN5A‐E1784K carrier (area under the curve, 0.692). There was good correlation between PR interval and SCN5A‐E1784K mutation carrier (area under the curve 0.842). Using a PR interval of 176 ms, sensitivity and specificity for identification of a SCN5A‐E1784K carrier was 76.5% and 72.2%. The best correlation was found for QTc interval. The cut‐off value of QTc=445 ms identified an SCN5A‐E1784K mutation carrier with a sensitivity of 88% and a specificity of 100% (area under the curve 0.993, Figure 2A).


Further Insights in the Most Common SCN 5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect
A, Receiver operating characteristic curve for PR interval, QRS duration, and QTc interval for the identification of SCN5A‐E1784K carriers vs noncarriers. The best correlation was found for QTc interval (area under the curve 0.993). B, Kaplan–Meier event‐free survival curves for SCN5A‐E1784K mutation carrier vs noncarriers are displayed. Noncarriers had no cardiac events. Four mutation carriers developed sudden cardiac arrest and ventricular fibrillation beyond the age of 40 years.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015375&req=5

jah31596-fig-0002: A, Receiver operating characteristic curve for PR interval, QRS duration, and QTc interval for the identification of SCN5A‐E1784K carriers vs noncarriers. The best correlation was found for QTc interval (area under the curve 0.993). B, Kaplan–Meier event‐free survival curves for SCN5A‐E1784K mutation carrier vs noncarriers are displayed. Noncarriers had no cardiac events. Four mutation carriers developed sudden cardiac arrest and ventricular fibrillation beyond the age of 40 years.
Mentions: In the receiver operating characteristic analysis, QRS interval was not found to be predictive for the identification of an SCN5A‐E1784K carrier (area under the curve, 0.692). There was good correlation between PR interval and SCN5A‐E1784K mutation carrier (area under the curve 0.842). Using a PR interval of 176 ms, sensitivity and specificity for identification of a SCN5A‐E1784K carrier was 76.5% and 72.2%. The best correlation was found for QTc interval. The cut‐off value of QTc=445 ms identified an SCN5A‐E1784K mutation carrier with a sensitivity of 88% and a specificity of 100% (area under the curve 0.993, Figure 2A).

View Article: PubMed Central - PubMed

ABSTRACT

Background: Phenotypic overlap of type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), cardiac conduction disease (CCD), and sinus node dysfunction (SND) is observed with SCN5A mutations. SCN5A‐E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype–phenotype relationship in a large family carrying SCN5A‐E1784K and SCN5A‐H558R polymorphism.

Methods and results: Clinical work‐up, follow‐up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A‐E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A‐H558R did not significantly alter the phenotype of SCN5A‐E1784K carriers. Fourteen SCN5A‐E1784K patients underwent implantable cardioverter‐defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8±3 months of follow‐up. One patient without ICD also developed VF after 6.7 years. These 5 cases carried both SCN5A‐E1784K and SCN5A‐H558R. Functional characterization was achieved by expressing SCN5A variants in TSA201 cells. Peak (INa,P) or late (INa,L) sodium currents were recorded using whole‐cell patch‐clamp techniques. Co‐expression of SCN5A‐E1784K and SCN5A‐WT reduced INa,P to 70.03% of WT, shifted steady‐state inactivation by −11.03 mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A‐E1784K was co‐expressed with SCN5A‐H558R.

Conclusions: We demonstrate a strong genotype‐phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A‐E1784K mutation described so far. Phenotype of LQTS is present during all decades of life, whereas CCD develops with increasing age. Phenotypic overlap may explain the high event rate in carriers.

No MeSH data available.


Related in: MedlinePlus