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Chen et al identified R1193Q, a single nucleotide polymorphism (SNP), in the cardiac sodium channel gene SCN5A, in a group of Han Chinese individuals. The frequency of SNP R1193Q in this Chinese population is high, reaching 12% (11/94).1 The results confirm our earlier report that SNP R1193Q is present in the general population.2 SNP R1193Q occurs within the context of a CpG dimer. Because most methylation in human DNA occurs at the C in the CpG dimer, it will interfere with efficient correction of C to T transitions resulting from 5-methyl cytosine deamination, making R1193 a potential hotspot for mutation.3
SCN5A is one of the disease causing genes for long QT syndrome (LQTS), a cardiac disorder characterised by a prolonged QT interval on electrocardiogram (ECG).4,5 LQTS patients have a high risk of syncope and sudden death due to a specific ventricular tachyarrhythmia, torsade de pointes. LQTS can be classified into two types, congenital LQTS or acquired LQTS. Congenital LQTS is uncommon, but acquired LQTS is common and may be present in more than 8% of the general population.2
Congenital LQTS is caused by genetic defects. To date, more than 250 different disease causing mutations in six genes, KvLQT1 (or KCNQ1), HERG (or KCNH2), SCN5A, ANKB, KCNE1, and KCNE2, have been identified in LQTS patients and families, and mutations in these genes may account for approximately 50–75% of congenital LQTS cases.6 Mutations in KvLQT1, KCNE1, KCNJ2, and HCN4 were also identified in congenital LQTS patients associated with other symptoms, including deafness (KvLQT1, KCNE1), periodic paralysis (KCNJ2), and sinus node dysfunction (HCN4).6,7 Acquired LQTS is caused by drugs and other environmental factors.2 To be accurate, the pathogenesis of acquired LQTS is caused by the interaction between genetic factors (for example, mutations) and environmental factors (for example, drugs). Acquired LQTS is mostly sporadic, which makes it challenging to identify its genetic factors using classical linkage analysis and positional cloning. Thus, several studies used the candidate gene approach, focusing on the genes responsible for congenital LQTS. This approach appears to be effective. Multiple SNPs in KvLQT1, HERG, SCN5A, KCNE1, and KCNE2 have been identified in patients with acquired LQTS (table 1). These studies provide evidence for the hypothesis that acquired and congenital LQTS may share the same genetic basis, and acquired LQTS may represent a latent form of congenital LQTS.
Chen et al report that one of nine carriers with SNP R1193Q is affected with congenital LQTS (QTc = 472 ms).1 This finding is consistent with our results from electrophysiological studies of mutant R1193Q sodium channels. We identified SCN5A SNP R1193Q in one of seven patients with acquired LQTS.2 As with other similar reported studies, it is difficult to provide definitive genetic evidence that R1193Q is a cause of acquired LQTS; an alternative is to provide functional or physiological evidence. We performed detailed electrophysiological characterisation of SNP R1193Q on the whole cell or single channel levels in both Xenopus oocytes and mammalian HEK293 cells. Distinct differences were observed between wild type and mutant R1193Q sodium channels. Similar to two other well-characterised mutations, N1325S and R1644H, which cause congenital LQTS, SNP R1193Q leads to the generation of a late-phase persistent non-inactivating sodium current and frequent dispersed reopenings of the channels on the single channel level.2,8,9 These results predict that R1193Q is capable of causing congenital LQTS, a conclusion now supported by the finding of Chen et al that one R1193Q carrier from a general population is affected with congenital LQTS.1 Thus, R1193Q is associated with both congenital and acquired LQTS. Three other mutations, KvLQT1 R555C, SCN5A S1103Y, and SCN5A V1667I are also associated with both congenital and acquired LQTS (table 1).
How to explain the finding that several carriers with SNP R1193Q have normal QTc or borderline QT interval prolongation? The penetrance of mutations associated with LQTS is highly variable. Many individuals with LQTS mutations display a normal QT interval or borderline QTc.4,10 These individuals are, however, at risk of developing LQTS, ventricular arrhythmias, and sudden death when exposed to drugs or other environmental stimuli. It would be interesting to test whether individuals who have a normal phenotype but carry SCN5A SNP R1193Q display LQTS when exposed to quinidine or sotalol. Furthermore, if the allele frequency of Q1193 is 6% in the Chinese population, a case-control association study could be designed to estimate the risk of this variant for arrhythmias in this population (note that a case-control study is unrealistic with an allele frequency of 0.1% in the Caucasian population).
The low frequency of 0.2% in a mostly Caucasian population and a high 12% rate of SNP R1193Q in a Chinese population may reflect an ethnic difference. It is important, however, to note that Xie et al sequenced the SCN5A gene in 120 unrelated Han Chinese individuals but did not report the identification of R1193Q in their samples.11 SNP R1193Q was also identified in a normal Japanese population (1/48 = 2%),12 which contradicts the report by Vatta et al that the variant was not present in 100 Japanese controls (however, note that the variant was mislabelled in the Vatta et al report).13 Therefore, more studies with much larger sample sizes are required to obtain an accurate estimate of the true frequency of SNP R1193Q in the Chinese and Japanese populations.
In summary, SNP R1193Q of the cardiac sodium channel gene SCN5A is present in several general populations, although its prevalence rate varies with different ethnic background, ranging from 0.2% to 12%. Electrophysiological characteristics of R1193Q predict that individuals carrying R1193Q are at increased risk of developing LQTS. Genetic studies provide supportive evidence for this prediction, but more studies are clearly warranted to estimate the relative risk or risk ratio for this variant.
Conflict interests: none declared.
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