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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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Related in: MedlinePlus

Basal ECGs of patient II,6. The ECGs show QTc prolongation, intermittent saddle‐back type Brugada ECG in the right precordial leads, and progressive conduction disease. The patient developed second‐degree atrioventricular block at the age of 78 years. A, Age 64: PR 193 ms, QRS 85 ms, QTc 461 ms. B, Age 75: PR 205 ms, QRS 94 ms, QTc 467 ms. C, Age 77: PR 229 ms, QRS 95 ms, QTc 472 ms. D, Age 78: Second‐degree AV block, QRS 104 ms, QTc 465 ms. E, Age 81: DDD pacemaker ECG.
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jah31596-fig-0003: Basal ECGs of patient II,6. The ECGs show QTc prolongation, intermittent saddle‐back type Brugada ECG in the right precordial leads, and progressive conduction disease. The patient developed second‐degree atrioventricular block at the age of 78 years. A, Age 64: PR 193 ms, QRS 85 ms, QTc 461 ms. B, Age 75: PR 205 ms, QRS 94 ms, QTc 467 ms. C, Age 77: PR 229 ms, QRS 95 ms, QTc 472 ms. D, Age 78: Second‐degree AV block, QRS 104 ms, QTc 465 ms. E, Age 81: DDD pacemaker ECG.

Mentions: Patient II,6, the mother of the proband, was an obligate mutation carrier. Repetitive ECG recordings at the age of 64, 75, 77, 78, and 81 were available (Figure 3). She developed progressive conduction disease with increasing age. At the age of 75, the patient showed first‐degree AVB and 3 years later second‐degree AVB. Consecutively, a DDD pacemaker was implanted due to symptomatic bradycardia due to sinus node dysfunction (SND) and second‐degree AVB. Furthermore, intermittent ST‐segment elevation in lead V1 (typical saddle‐back type for the BrS), was visible (Figure 3B).


Further Insights in the Most Common SCN 5A Mutation Causing Overlapping Phenotype of Long QT Syndrome, Brugada Syndrome, and Conduction Defect
Basal ECGs of patient II,6. The ECGs show QTc prolongation, intermittent saddle‐back type Brugada ECG in the right precordial leads, and progressive conduction disease. The patient developed second‐degree atrioventricular block at the age of 78 years. A, Age 64: PR 193 ms, QRS 85 ms, QTc 461 ms. B, Age 75: PR 205 ms, QRS 94 ms, QTc 467 ms. C, Age 77: PR 229 ms, QRS 95 ms, QTc 472 ms. D, Age 78: Second‐degree AV block, QRS 104 ms, QTc 465 ms. E, Age 81: DDD pacemaker ECG.
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jah31596-fig-0003: Basal ECGs of patient II,6. The ECGs show QTc prolongation, intermittent saddle‐back type Brugada ECG in the right precordial leads, and progressive conduction disease. The patient developed second‐degree atrioventricular block at the age of 78 years. A, Age 64: PR 193 ms, QRS 85 ms, QTc 461 ms. B, Age 75: PR 205 ms, QRS 94 ms, QTc 467 ms. C, Age 77: PR 229 ms, QRS 95 ms, QTc 472 ms. D, Age 78: Second‐degree AV block, QRS 104 ms, QTc 465 ms. E, Age 81: DDD pacemaker ECG.
Mentions: Patient II,6, the mother of the proband, was an obligate mutation carrier. Repetitive ECG recordings at the age of 64, 75, 77, 78, and 81 were available (Figure 3). She developed progressive conduction disease with increasing age. At the age of 75, the patient showed first‐degree AVB and 3 years later second‐degree AVB. Consecutively, a DDD pacemaker was implanted due to symptomatic bradycardia due to sinus node dysfunction (SND) and second‐degree AVB. Furthermore, intermittent ST‐segment elevation in lead V1 (typical saddle‐back type for the BrS), was visible (Figure 3B).

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