The Brugada Syndrome: A Rare Arrhythmia Disorder with Complex Inheritance

Abstract

For the last 10 years, applying new sequencing technologies to thousands of whole exomes has revealed the high variability of the human genome. Extreme caution should thus be taken to avoid misinterpretation when associating rare genetic variants to disease susceptibility. The Brugada syndrome (BrS) is a rare inherited arrhythmia disease associated with high risk of sudden cardiac death in the young adult. Familial inheritance has long been described as Mendelian, with autosomal dominant mode of transmission and incomplete penetrance. However, all except 1 of the 23 genes previously associated with the disease have been identified through a candidate gene approach. To date, only rare coding variants in the SCN5A gene have been significantly associated with the syndrome. However, the genotype/phenotype studies conducted in families with SCN5A mutations illustrate the complex mode of inheritance of BrS. This genetic complexity has recently been confirmed by the identification of common polymorphic alleles strongly associated with disease risk. The implication of both rare and common variants in BrS susceptibility implies that one should first define a proper genetic model for BrS predisposition prior to applying molecular diagnosis. Although long remains the way to personalized medicine against BrS, the high phenotype variability encountered in familial forms of the disease may partly find an explanation into this specific genetic architecture.

Optimal management of Brugada syndrome

“…The mutations are inherited in an autosomal dominant manner, with incomplete penetrance [9]. The dominant susceptibility gene is SCN5A, which encodes the alpha subunit of a myocardial sodium channel [10]. The overall prevalence of SCN5A mutations is 20-25%, but SCN5A variants are even more frequent among children with BrS [11].…”

Brugada Syndrome: Evolving Insights and Emerging Treatment Strategies

“…13 Beyond SCN5A, an additional 22 genetic culprits have been identified as predisposing a patient to developing BrS (Table 1). 5 Consistent with BrS' being reflective of a channelopathy, the majority of the culprits encode ion channels that mediate currents involved in the cardiac action potential. SCN10A encodes a neuronal sodium channel, while SCN1B, SCN2B, and SCN3B encode b-subunits that modulate Nav1.5.…”

“…3 Since its original description approximately 25 years ago, significant progress has been made towards unraveling BrS's mechanistic underpinnings, including the identification of the 23 genes suggested to predispose individuals to its development. 2,4,5 Despite having made considerable strides forward in the understanding of the condition, critical gaps continue to persist, making efficient clinical management of affected individuals challenging. 6 An underlying genetic culprit continues to be elusive in the majority of patients, while discord regarding BrS's underlying pathophysiology persists, with strong lines of evidence available for both the ''depolarization'' and ''repolarization'' hypotheses.…”

“…6 An underlying genetic culprit continues to be elusive in the majority of patients, while discord regarding BrS's underlying pathophysiology persists, with strong lines of evidence available for both the ''depolarization'' and ''repolarization'' hypotheses. 5,7 For clinicians, a major challenge that remains is the effective risk stratification of asymptomatic patients who, by guidelines, are currently managed with observation. and safer, more effective treatment options.…”

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“…beta-adrenergic blockage, sodium channel blockade, calcium channel blockade, and repolarization prolongation. [98] It is reported to stimulate intestinal movements and respiration. Its action on pulmonary and systemic blood pressure is similar to that of serpentine.…”