Some Advances on Genetics Related to Brugada Syndrome

PAN Jie*, HU Kang-xin and YAO Wen-liang

Nanchang City Institute of Medical Sciences, Nanchang, China

*Corresponding author: PAN Jie, Nanchang City Institute of Medical Sciences, Nanchang, China

Received: November 18, 2015; Accepted: January 21, 2016; Published: January 22, 2016

Abstract

Brugada Syndrome (BrS) is a rare inherited arrhythmogenic disorder that exhibits ECG ST-segment elevation=2mm with a negative T-wave in the right precordial leads (V1-V2), with normal heart structure, predisposing to Ventricular Fibrillation (VF) and Sudden Cardiac Death (SCD). Genetically BrS is autosome dominant accompanied by incomplete penetrance, and mutations in SCN5A gene had been identified as the main pathogenic cause of BrS. Besides, mutations of other 16 genes also link to BrS, but mutation in SCN5A account for approximately 30% and those in other genes 5% leaving no definitive genetic background in 65% of BrS patients. Some advances on genetics related to BrS are reviewed in this paper.

Keywords: Brugada syndrome; Genetics; SCN5A; Gene mutation

Introduction

BrS is a rare inherited arrhythmogenic disorder that exhibits ECG ST-segment elevation=2mm with a negative T-wave in the right precordial leads (V1-V2), with normal heart structure, predisposing to Ventricular Fibrillation (VF) and Sudden Cardiac Death (SCD). In 1992, Brugada P and Burgada J first discovered it as a new arrhythmia. After SCN5A was identified as the first pathogenic gene of BrS [1-3] in 1998, it was learned that BrS is an autosomal dominant inheritance accompanied by incomplete penetrance.

Retrospect of Researches on BrS in Past Ten Years [1]

From 1998 to 2008, 6 gene mutations were found associated with BrS, in which 4 gene mutations were reported in 2008.The first gene mutation is SCN5A intronic mutation activated by cryptic splice site in a family with BrS, resulting loss-of-function of Na⁺ channel. The second site is in autosome 3 [1] (similar but different from SCN5A), it has been linked to a large family with BrS, accompanied by syndrome of progressive conduct disease. This gene was called glycerol-3- phophate dehydrogenase like gene (GPDIL). GPDIL mutation is at least partly caused by membrane transport defect. Afterwards, the third and the fourth genes code α₁ subunit (CACNA1C) and β subunit (CANB2β) of L type cardiacCa²⁺ channel, respectively. The mutations in α and β subunits of cardiacCa²⁺ channel are usually accompanied by familial sudden cardiac death syndrome. See following (Table 1).

Table 1: Genetic Basis of BrS.




  
    Researcher
    Type
    Site
    lon Channel
    Gene
    Protein
    Incidence (%)
  
  
    Chen, et al.,
    BrS1
    3p21
    I_No
    SCN5A
    Nav1.5
    15
  
  
    London, et al.,
    BrS2
    3p24
    I_No
    GPD1L
    -
    Rare
  
  
    Antzelevitch, et al,.
    BrS3
    12p13.3
    I_Ca
    CACNA1C
    Cav1.2
    6.6
  
  
    Antzelevitch, et al.,
    BrS4
    10p12.33
    I_Ca
    CACNB2b
    Cavβ₂1
    4.8
  
  
    Watanabe
    BrS5
    19q13.1
    I_No
    SCN1B
    Navβ₁
    1.1
  
  
    Delpon, et al.,
    BrS6
    11q13-q14
    Ito
    KCNE3
    MiPR2
    Rare



Table 1:  Genetic Basis of BrS.

Research Status on Brugada Syndrome in Recent 3 Years

Research advances in 2013

Hsiao et al., [4] systematically mentioned the genetic aspects related to BrS when reviewing ion channelopathies. They reported that 11 gene mutations had been identified in BrS. These mutations locate in SCN5A (coding Nav1.5), SCN1B and SCN3B (coding cardiac Na⁺ channel β subunit) or GPD1L and MOG1 (involving Nav1.5 to membrane transport). All of them cause loss-of-function of Nav1.5, thereby decreasing I_Na. Other mutations locate in CACN1C, CACNB2b and CACNA2D1 respectively (coding α₁α₁, β_2b and α₂d₁ subunits of Cav1.2, respectively), leading to the decrease of L type Ca²⁺ current (I_CaL), KCNE3 (coding MiRP2, α and β subunits of several K⁺ channels) and KCNJ8 (coding ATP-sensitive K⁺ channel). In a word, SCN5A mutation accounts for approximately 20% BrS patients, mutations in other genes account for only 10%, the remaining 70% BrS patients have not found definitive genetic background.

Research advances in 2014

Brugada, et al., [3] revealed that 16 genes (SCN5A, GPDIL, SCN1B, SCN2B, SCN3B, RANGRF, SLM4P, KCNE3, KCNJ8, KCNE4, KCNE5, KCND3, CACN1C, CACNB2b, CACNA2D1 and TPPM4) 350 mutations had been reported until 2014. These genes code cardiac Na⁺, K⁺ andCa²⁺ channels, respectively, and are involved in transport or regulation of these channels. Even though the number of genes is high, they are the pathogenic cause of only about 35% BrS patients, in which mutations of SCN5A gene account for approximate 30%, mutations of other genes only 5%. The remaining 65% patients cannot find a genetic source. Hence, the achievement on genetic researches of BrS in 2014 is good: pathogenic genes were found 5 more than in 2013. Several factors in gene screening may account for the cause of BrS patients without genetic source, such as the change of replication number in SCN5A, in addition, pathogenic mutation may locate in undiscovered genes. BrS may be related to epigenetic factors, principally DNA methylation, post-translation modification and RNA mechanism. All these factors at least partly account for BrS mild incomplete penetrance and its variation expression characteristics.

Research advances in the first season of 2015

SCN10A Behr, et al., [5] studied 156 cases of Cancasus patients with SCN5A dominant negative BrS. They had identified 7 candidate genes (SCN10A, Handl, PLN, Casqz, TKT, TBX3 and TBX5) as variant in 49 cases, rare (MAF 1%) and non-synonymous in 18 cases, in which 11 cases were mostly SCN10A, predicting that it was pathogenic. Cosegregation showed that 4/7 cases carried new variant possibly, only 1 case had V/G 1299A in SCN10A and did not display co-segregation. However, single nucleotide polymorphism (SNP) V1073 in SCN10A was closely related to BrS. In frequent variants (V1073 and A1073) and rare variants (A200V and 1671V) of SCN10A, voltage-clamp test was carried out. The peak value of inward current of Na⁺ current (I_Na) decreased markedly, when compared with the ancestral allelles A1073 (rs795970). They concluded that when screening rare variant of QRS related genes (including SCN10A), most of them did not result in SCN10A dominant negative BrS. Frequnet SNP SCN10A V1073 were closely related to BrS, and Nav1.5 loss-of-function had been confirmed.

Genes coding variant burden La Souamee, et al., [6] determined rare gene coding variant burden in arrhythmia-sensitive genes of a large group of BrS patients. They captured and sequenced coding regions of arrhythmia-sensitive genes (reported previously) in 45 cases, by using customized equipment. Through burden test, they observed a large quantity of coding variant only in SCN5A (the frequency of minor allele<0.1%). 20.09% BrS patients and 24% controls carried rare coding variant, whereas in any other arrhythmiasensitive genes (including SCN10A and CACNA1C), they did not found a large quantity of coding variant. These results indicated that except SCN5A, rare coding variant in arrhythmia-sensitive genes reported previously is related to European ancestry individuals with BrS. In case of molecular diagnosis, it should be doubly careful to explain the genetic variation, because coding variant of BrS-sensitive genes can be observed in the same number of patients and controls.

New genetic variants found in SCN5A Saber, et al., [7] had proposed that at least 17 genes linked to patients with BrS, although recent findings reveal its polygenic background. They found that SCN5A carried new genetic variant p.P1506S in BrS patients of a large Irish family. From clinical, genetic and expressive researches, they observed availability curve hyper polarization shift, activation curve depolarization shift and promoting rapid inactivation process. The change induced by these mutations resulted in loss-of-function of Nav1.5, in this way, p.P1506S variant is pathogenic. In addition, cascade familial screening discovered that BrS family members did not carry p.P1506S mutation within KCNH2 gene in SCN5A-neative patients. These finding clarified complex genetic background as well as possible pathogenic role of new SCN5A genetic variant in this family. In genetic examination of SCN5A in 6 Polish BrS patients with ajmaline provocation test positive, Uzieblo-Zyczkowska [8] revealed 6 kinds of known polymorphism, 8 new single nucleotide points (SNP), whose variants locate in the exons, 12 new SNPs locating in the introns. Three new SNPs in SCN5A gene exon influenced protein sequence.

Newly Discovered Gene Mutations in SCN5A

Hsuch,et al., [9] reported 3 new SCN5A mutations in Taiwan area, ie. p.1848fs, p. R965C and p.1876insM. p. 1848fs mutation did not produce Na⁺ current. The latter two mutations produced steady-state inactivation channels shifting toward negative potential (19.4mV and 8mV, respectively) as well as a slower recovery time. p.1876insM steadied the activation change shifting toward positive potential (7.69mV). They considered that SCN5A channel defect related to BrS might be different, but all gave rise to Na⁺ current reduction. Zeng, et al., [10] found dominant missense mutation (R1629Q) locating in DIV-S4 in a Chinese Han family. They identified such mutation from DNA of proband by using SCN5A direct sequencing. They also identified steady-state inactivation curve hyperpolaization shift in cells expressing R1629Q channel. R1629Q channel manifested intermediate inactivation enhance as well as time extension from inactivation to recovery. Their research showed that R1629Q mutation lead to loss-of-function in channels due to the change of channel electrophysiological characteristics. Tarrades, et al., [11] showed that new 1890T mutation of SCN5A located in pore region of Nav1.5, leading to definite loss-of-function in channels. It seemed that BrS phenotype observed in proband is most likely due to this mutation. Antzelevitch and Nof [1] reported the additional actions of 2 heterozygote missence mutations in SCN5A:p336L mutation in SCN5A resulting in I_Na decrease, whereas 116201 mutation terminating I_Na. Only in proband who carries these 2 mutations simultaneously, BrS phenotype can display, in which any one mutation alone cannot produce clinical phenotype in father or daughter of proband. Saber, et al., [12] found that delKPQ1505-1507 mutation known in SCN5A gene not only showed LQTS phenotype, but also its carrier appeared LQTS and BrS simultaneously (Joint phenotype). This overlapping phenotype has high risk of sudden cardiac death. Zakzliazminskaia, et al., [13] reported 25 Russian patients with BrS. They found SCN5A rare genetic variants in 7/24 probands in which 2 cases involved protein splice (eIVS16DS-5A>G and cIVS24A+1G>A) 3 cases had missence mutation (p.Y87C, p.R93H,p.S1787N),1 case had in-frame deletion p.del 18481, and 1 case had nonsense mutation pE553X.

SCN1B and SCN3B

So far, there are 17 genes linked to BrS. Besides SCN5A has been well known, SCN10A and GPDIL were introduced just now. The remaining 14 genes can only introduce SCN1B and SCN2B here, the rest are not quite clear in the literature. Ricci, et al., [14] studied SCN1B, which codes voltage-gating β₁ subunit and its soluble β₁_b isoform in Na⁺ channel. They found that SCN1B mutation had been accompanied by BrS and other arrhythmia, familial epilepsy. They analyzed exon 3A & 3\UTR of SCN1B in 145 SCN5A-negative patients, and found 2 new SCN1B variants. Their findings contribute more evidence that SCN1B variants occur in BrS.

Ishikawa, et al., [15] studied a total of 181 BrS patients without SCN5A mutation. In 3 Japanese patients, SCN3B mutation (Val750lle) was identified. SCN3B mutation damages cytoplasm transport. Na⁺ current decreases obviously. They considered Val750lle mutation in SCN3B as a relatively common cause of Japanese SCN5A-negative BrS patients, because Nav1.5 cell surface expression defect leads to Na⁺ current decrease. Hu, et al., [16] support the hypothesis that SCN3B can cause Nav1.5 protein transport function expression defect, which results in Na⁺ channel current decrease and hence show clinical phenotype of BrS.

References

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Citation: PAN Jie, HU Kang-xin and YAO Wen-liang. Some Advances on Genetics Related to Brugada Syndrome. Austin Cardio & Cardiovasc Case Rep. 2016; 1(1): 1004.

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