SCN5A Mutations and the Role of Genetic Background in the Pathophysiology of Brugada Syndrome

Abstract

Background-Mutations in SCN5A are identified in Ϸ20% to 30% of probands affected by Brugada syndrome (BrS).However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families. Methods and Results-Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECGϩ; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECGϩ). Among these 8 mutation-negative BrS-ECGϩ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects. Conclusions-Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECGϩ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels. (Circ Cardiovasc Genet. 2009;2:552-557.)

Genetics can contribute to the prognosis of Brugada syndrome: a pilot model for risk stratification

“…Indeed, the classical concept of BrS as a mendelian disease has been recently modified according to the idea of arrhythmia genomics, suggesting that different variants may contribute to the phenotype and sodium channel defects may be one of the contributory causes and not necessarily the main. 7,41 Inter-individual genetic differences may modulate excitation-contraction physiology, influencing arrhythmia susceptibility and may even explain differences in clinical phenotype presentation among distinct ethnicities. 42,43 Ion channels carry out their function as part of multiproteic complexes, interacting with accessory subunits and regulatory proteins.…”

Ionic and Cellular Mechanisms Underlying the Development of Acquired Brugada Syndrome in Patients Treated with Antidepressants

“…36 Recently it has been reported that SCN5A mutation are not directly causal for BrS phenotype. 37 We need to consider other genetic effects because the balance of all currents active during the early phases of the AP recapitulate the BrS phenotype. Each genetic background of the patient can lead different phenotype by amitriptyline.…”

The role of genetic testing in unexplained sudden death

“…67 In addition, there are large SCN5A positive families that have affected individuals who are noncarriers, suggesting a modifier role rather than direct causation in these pedigrees. 86 Many other genes have been associated with the syndrome (Table I). One study identified mutations of the L-type calcium channel (encoded by CACNA1C, CACNB2B, and CACNA2D1) in 10%-15% of BrS cases.…”