Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants.
J Am Coll Cardiol
; 78(16): 1603-1617, 2021 10 19.
Article
en En
| MEDLINE
| ID: mdl-34649698
ABSTRACT
BACKGROUND:
Two major forms of inherited J-wave syndrome (JWS) are recognized early repolarization syndrome (ERS) and Brugada syndrome (BrS).OBJECTIVES:
This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.METHODS:
Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure.RESULTS:
The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%.CONCLUSIONS:
These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Potenciales de Acción
/
Predisposición Genética a la Enfermedad
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Síndrome de Brugada
/
Sistema de Conducción Cardíaco
Tipo de estudio:
Prognostic_studies
Límite:
Adult
/
Female
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Humans
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Male
Idioma:
En
Revista:
J Am Coll Cardiol
Año:
2021
Tipo del documento:
Article
País de afiliación:
China