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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.

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Functional expression studies evaluating the characteristics of late INa for WT+WT, E1784K+WT, and E1784K+H558R. A, Representative TTX‐sensitive sodium current traces obtained by subtraction, recorded during a 300‐ms depolarization to −20 mV from −120 mV (left panel). Amplified traces showing late INa (right panel). B and C, Bar graph of relative late INa (% of peak INa) and late INa density (pA/pF) among 3 groups. Statistically significant differences (*P<0.05) were observed between E1784K+WT/E1784K+H558R and WT+WT in both panels (n=7, 10, 22 for each group). No statistically significant difference was observed between E1784K+WT and E1784K+H558R. For values see text.
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jah31596-fig-0006: Functional expression studies evaluating the characteristics of late INa for WT+WT, E1784K+WT, and E1784K+H558R. A, Representative TTX‐sensitive sodium current traces obtained by subtraction, recorded during a 300‐ms depolarization to −20 mV from −120 mV (left panel). Amplified traces showing late INa (right panel). B and C, Bar graph of relative late INa (% of peak INa) and late INa density (pA/pF) among 3 groups. Statistically significant differences (*P<0.05) were observed between E1784K+WT/E1784K+H558R and WT+WT in both panels (n=7, 10, 22 for each group). No statistically significant difference was observed between E1784K+WT and E1784K+H558R. For values see text.

Mentions: E1784K and H558R channels were also evaluated for late INa (Figure 6A). TTX‐sensitive currents were compared at the end of a 300‐ms depolarization, and values were obtained by subtracting the values before and after TTX. Summary data for late INa, presented as percent of peak INa, were significantly higher when E1784K was expressed (1.86±0.23% co‐expressed with WT, n=7; 1.89±0.25% co‐expressed with H558R, n=10), compared with the WT group (0.14±0.02%, n=22; Figure 6B). Moreover, late INa amplitude recorded from the E1784K channel, with WT or H558R, was also obviously larger than in WT. Late INa density was 1.30±0.29 pA/pF (n=22) for WT+WT channels, 9.91±2.48 pA/pF (n=7) for E1784+WT and 8.53±1.63 pA/pF (n=10) for E1784+H558R mutant channels (Figure 6C). H558R variant did not significantly alter increased late INa produced by SCN5A‐E1784K mutation.


Further Insights in the Most Common SCN 5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect
Functional expression studies evaluating the characteristics of late INa for WT+WT, E1784K+WT, and E1784K+H558R. A, Representative TTX‐sensitive sodium current traces obtained by subtraction, recorded during a 300‐ms depolarization to −20 mV from −120 mV (left panel). Amplified traces showing late INa (right panel). B and C, Bar graph of relative late INa (% of peak INa) and late INa density (pA/pF) among 3 groups. Statistically significant differences (*P<0.05) were observed between E1784K+WT/E1784K+H558R and WT+WT in both panels (n=7, 10, 22 for each group). No statistically significant difference was observed between E1784K+WT and E1784K+H558R. For values see text.
© Copyright Policy - creativeCommonsBy-nc-nd
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5015375&req=5

jah31596-fig-0006: Functional expression studies evaluating the characteristics of late INa for WT+WT, E1784K+WT, and E1784K+H558R. A, Representative TTX‐sensitive sodium current traces obtained by subtraction, recorded during a 300‐ms depolarization to −20 mV from −120 mV (left panel). Amplified traces showing late INa (right panel). B and C, Bar graph of relative late INa (% of peak INa) and late INa density (pA/pF) among 3 groups. Statistically significant differences (*P<0.05) were observed between E1784K+WT/E1784K+H558R and WT+WT in both panels (n=7, 10, 22 for each group). No statistically significant difference was observed between E1784K+WT and E1784K+H558R. For values see text.
Mentions: E1784K and H558R channels were also evaluated for late INa (Figure 6A). TTX‐sensitive currents were compared at the end of a 300‐ms depolarization, and values were obtained by subtracting the values before and after TTX. Summary data for late INa, presented as percent of peak INa, were significantly higher when E1784K was expressed (1.86±0.23% co‐expressed with WT, n=7; 1.89±0.25% co‐expressed with H558R, n=10), compared with the WT group (0.14±0.02%, n=22; Figure 6B). Moreover, late INa amplitude recorded from the E1784K channel, with WT or H558R, was also obviously larger than in WT. Late INa density was 1.30±0.29 pA/pF (n=22) for WT+WT channels, 9.91±2.48 pA/pF (n=7) for E1784+WT and 8.53±1.63 pA/pF (n=10) for E1784+H558R mutant channels (Figure 6C). H558R variant did not significantly alter increased late INa produced by SCN5A‐E1784K mutation.

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&#8208;E1784K is the most common mutation associated with BrS and LQTS3. The present study examines the genotype&ndash;phenotype relationship in a large family carrying SCN5A&#8208;E1784K and SCN5A&#8208;H558R polymorphism.

Methods and results: Clinical work&#8208;up, follow&#8208;up, and genetic analysis were performed in 35 family members. Seventeen were SCN5A&#8208;E1784K positive. They also displayed QTc prolongation, and either BrS, CCD, or both. One carrier exhibited SND. The presence of SCN5A&#8208;H558R did not significantly alter the phenotype of SCN5A&#8208;E1784K carriers. Fourteen SCN5A&#8208;E1784K patients underwent implantable cardioverter&#8208;defibrillator (ICD) implantation; 4 developed VF and received appropriate ICD shocks after 8&plusmn;3&nbsp;months of follow&#8208;up. One patient without ICD also developed VF after 6.7&nbsp;years. These 5 cases carried both SCN5A&#8208;E1784K and SCN5A&#8208;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&#8208;cell patch&#8208;clamp techniques. Co&#8208;expression of SCN5A&#8208;E1784K and SCN5A&#8208;WT reduced INa,P to 70.03% of WT, shifted steady&#8208;state inactivation by &minus;11.03&nbsp;mV, and increased INa,L from 0.14% to 1.86% of INa,P. Similar changes were observed when SCN5A&#8208;E1784K was co&#8208;expressed with SCN5A&#8208;H558R.

Conclusions: We demonstrate a strong genotype&#8208;phenotype correlation with complete penetrance for BrS, LQTS, or CCD in the largest family harboring SCN5A&#8208;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