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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.


Clinical summary of the affected family. A, Pedigree of the family. B, Baseline ECG of the index patient (proband), who is positive for SCN5A‐E1784K and H558R. C, PR interval vs QTc among SCN5A‐E1784K carriers. Upper limit of normal values is indicated by dotted lines.
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jah31596-fig-0001: Clinical summary of the affected family. A, Pedigree of the family. B, Baseline ECG of the index patient (proband), who is positive for SCN5A‐E1784K and H558R. C, PR interval vs QTc among SCN5A‐E1784K carriers. Upper limit of normal values is indicated by dotted lines.

Mentions: The European family studied consisted of 76 family members (Figure 1). All members were encouraged to undergo a complete clinical work‐up and follow‐up. The work‐up included medical and family history, physical examination, 12‐lead baseline and stress ECG, and echocardiogram. ECGs were analyzed by 2 independent cardiologists blended to genotype status. In case of abnormal findings, invasive cardiologic investigations were performed. All members were invited to participate in an ajmaline challenge test and genetic screening for causative mutations. The clinical and genetic studies were approved by the local human ethics committees and performed after written informed consent was obtained from all participants. All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.


Further Insights in the Most Common SCN 5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect
Clinical summary of the affected family. A, Pedigree of the family. B, Baseline ECG of the index patient (proband), who is positive for SCN5A‐E1784K and H558R. C, PR interval vs QTc among SCN5A‐E1784K carriers. Upper limit of normal values is indicated by dotted lines.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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

jah31596-fig-0001: Clinical summary of the affected family. A, Pedigree of the family. B, Baseline ECG of the index patient (proband), who is positive for SCN5A‐E1784K and H558R. C, PR interval vs QTc among SCN5A‐E1784K carriers. Upper limit of normal values is indicated by dotted lines.
Mentions: The European family studied consisted of 76 family members (Figure 1). All members were encouraged to undergo a complete clinical work‐up and follow‐up. The work‐up included medical and family history, physical examination, 12‐lead baseline and stress ECG, and echocardiogram. ECGs were analyzed by 2 independent cardiologists blended to genotype status. In case of abnormal findings, invasive cardiologic investigations were performed. All members were invited to participate in an ajmaline challenge test and genetic screening for causative mutations. The clinical and genetic studies were approved by the local human ethics committees and performed after written informed consent was obtained from all participants. All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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.