SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families

Abstract

Background - Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods - Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms (SNP) previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132 and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 SNP risk alleles). Results - In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 4.15 for BrS phenotype (95%CI:1.45-11.85, p=0.0078). Amongst SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 2.35 (95%CI:0.89-6.22, p=0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded and OR of 22.29 (95%CI:1.84-269.30, p=0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an OR=5.12 (95%CI:1.93-13.62, p=0.0011). Conclusions - Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Brugada Syndrome: Warning of a Systemic Condition?

“…For example, idiopathic epilepsy and LQTS may be linked by mutations in the potassium channel gene, KCNQ1 (58). Also the sodium channel gene, SCN5A, usually associated with SCD and BrS (60-62), has been of particular interest to understand the effects of specific mutations (63)(64)(65)(66)(67)(68) or even polymorphisms (69)(70)(71)(72)(73) in this gene, and their relation with BrS, and this gene has been linked to sudden unexplained death in epilepsy (SUDEP) (74). In fact, this gene has already been implicated in an overlap syndrome involving both epilepsy and BrS (24).…”

Arrhythmia variant associations and reclassifications in the eMERGE-III sequencing study

“…Several variables help explain incomplete penetrance for arrhythmia disorders, such as genetic background (including common polygenic risk), sex, and age; environmental influences such as drug exposures and electrolyte derangements can also elicit a phenotype in susceptible individuals. 29-31 Future precision medicine efforts could integrate these variables with P/LP variant status to better identify individuals at high risk of developing serious arrhythmias.…”

Phenotypic variability and modifier variants in children with hereditary heart diseases

“…В группе из 312 пациентов с синдромом Бругада из 16 медицинских центров с использованием шкалы генетического риска было изучено распределение частых генетических вариантов, ранее ассоциированных с синдромом Бругада при проведении GWAS. Была показана кумулятивная ассоциация частых вариантов гена SCN5A с фенотипом, независимо от наличия патогенного каузативного варианта в этом гене [50].…”