Early-onset Lone Atrial Fibrillation Research Articles

P2860The effects of single nucleotide polymorphisms in Korean patients with early-onset lone atrial fibrillation after catheter ablation

Abstract Background The status of SNPs among patients with extremely early-onset lone AF and the association with outcome of catheter ablation has not been evaluated before. This study evaluated the status of single nucleotide polymorphisms (SNPs) in Korean patients with early-onset (<40 years old) lone AF and effects on the outcome after catheter ablation. Methods A total of 89 consecutive patients (mean age 35.7±3.7 years, 81 males) with drug-refractory AF (paroxysmal 64.0%) who underwent catheter ablation were included. Sixteen SNPs including rs13376333, rs10465885, rs10033464, rs2200733, rs17042171, rs6843082, rs7193343, rs2106261, rs17570669, rs853445, rs11708996, rs6800541, rs251253, rs3807989, rs11047543 and rs3825214 were genotyped. Serial 48-day Holter electrocardiographic recordings were acquired to detect AF recurrences during long-term follow up. Results Wild type of rs7193343 [CC; 0/7 (0%) vs. CT; 22/40 (55.0%) vs. TT; 18/41 (43.9%), p=0.025] and rs11047543 [GG; 26/69 (37.7%) vs. GA; 13/18 (72.2%) vs. AA; 0/0, p=0.009] and homozygous variant of rs3825214 [AA; 16/31 (51.6%) vs. AG; 22/43 (51.2%) vs. GG; 2/13 (15.4%), p=0.05] were significantly associated with lower rate of late recurrence. When the patients were assigned to four groups according to the number of risk alleles (n=0–3), Kaplan-Meier survival analysis showed incremental prognostic value according to the number of variant alleles (p=0.002) (Figure 1). Figure 1 Conclusions Polymorphisms on rs7193343, rs3825214 and rs11047543 modulate the risk for AF recurrence after catheter ablation during long term follow up in Korean patients with early-onset lone AF. Acknowledgement/Funding Korean Society of Cardiology

Genetic variants on chromosomes 7p31 and 12p12 are associated with abnormal atrial electrical activation in patients with early-onset lone atrial fibrillation.

Abnormal P-wave morphology (PWM) has been associated with a history of atrial fibrillation (AF) in earlier studies. Although lone AF is believed to have substantial genetic basis, studies on associations between single nucleotide polymorphisms (SNP) linked to lone AF and PWM have not been reported. We aimed to assess whether SNPs previously associated with lone AF (rs2200733, rs13376333, rs3807989, and rs11047543) are also linked to P-wave abnormalities. Four SNPs were studied in 176 unrelated individuals with early-onset lone AF (age at onset <50years), median age 38years (19-63years), 149 men. Using sinus rhythm ECG, orthogonal PWM was classified as Type 1-positive in leads X and Y and negative in lead Z, Type 2-positive in leads X and Y and biphasic (-/+) in lead Z, Type 3-positive in lead X and biphasic in lead Y (+/-), and the remaining as atypical. Two SNPs were found to be significantly associated with altered P-wave morphology distribution: rs3807989 near the gene CAV1/CAV2 and rs11047543 near the gene SOX5. Both SNPs were associated with a higher risk of non-Type 1 P-wave morphology (rs3807989: OR=4.8, 95% CI=2.3-10.2, p<0.001; rs11047543: OR=4.7, 95% CI=1.1-20.5, p=0.04). No association was observed for rs2200733 and rs13376333. In this study, the two variants rs3807989 and rs11047543, previously associated with PR interval and lone AF, were associated with altered P-wave morphology distribution in patients with early-onset lone AF. These findings suggest that common genetic variants may modify atrial conduction properties.

Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation

A family history of atrial fibrillation constitutes a substantial risk of developing the disease, however, the pathogenesis of this complex disease is poorly understood. We perform whole-exome sequencing on 24 families with at least three family members diagnosed with atrial fibrillation (AF) and find that titin-truncating variants (TTNtv) are significantly enriched in these patients (P = 1.76 × 10−6). This finding is replicated in an independent cohort of early-onset lone AF patients (n = 399; odds ratio = 36.8; P = 4.13 × 10−6). A CRISPR/Cas9 modified zebrafish carrying a truncating variant of titin is used to investigate TTNtv effect in atrial development. We observe compromised assembly of the sarcomere in both atria and ventricle, longer PR interval, and heterozygous adult zebrafish have a higher degree of fibrosis in the atria, indicating that TTNtv are important risk factors for AF. This aligns with the early onset of the disease and adds an important dimension to the understanding of the molecular predisposition for AF.

Functional consequences of genetic variation in sodium channel modifiers in early onset lone atrial fibrillation.

We investigated the effect of variants in genes encoding sodium channel modifiers SNTA1 and GPD1L found in early onset atrial fibrillation (AF) patients. Genetic screening in patients with early onset lone AF revealed three variants in GPD1L and SNTA1 in three AF patients. Functional analysis was performed by patch-clamp electrophysiology. Co-expression of GPD1L or its p.A326E variant with NaV1.5 did not alter INa density or current kinetics. SNTA1 shifted the peak-current by -5mV. The SNTA1-p.A257G variant significantly increased INa. SNTA1-p.P74L did not produce functional changes. Although genetic variation of sodium channel modifiers may contribute to development of AF at a molecular level, it is unlikely a monogenic cause of the disease.

A novel KCND3 mutation associated with early-onset lone atrial fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia in the clinic. While previous studies have identified AF-associated mutations in several genes, the genetic basis for AF remains unclear. Here, we identified a novel T361S missense mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) from a Chinese Han family ancestor with lone AF. The wild-type (WT) or mutant T361S of Kv4.3 protein (encoded by KCND3) were co-expressed with the auxiliary subunit K+ channel-Interacting Protein (KChIP2) in HEK293 cells, and transient outward potassium current (Ito) were recorded using patch-clamp methods, and the surface or total protein levels of Kv4.3 were analyzed by western blot. Ito density, measured at 60 mV, for T361S was significantly higher than that for WT. Both the steady-state activation and inactivation curves showed a remarkable hyperpolarizing shift in T361S. Moreover, recovery from inactivation after a 500-ms depolarizing pulse was significantly delayed for T361S compared with that for WT. Mechanistically, the gain of function of Ito elicited by T361S was associated with the increased expression of cell surface and total cell protein of Kv4.3. The computer stimulation revealed that the T361S mutation shortened the action potential duration through an increased Itoin Human Atrial Model. In conclusion, we identified a novel T361S mutation in KCND3 associated with AF in the Chinese Han family. The T361S mutant result in the changes in channel kinetics as well as the up-regulation of Kv4.3 protein, which may be a critical driver for lone AF as observed in the patient.

Generation of induced pluripotent stem cells (iPSC) from an atrial fibrillation patient carrying a KCNA5 p.D322H mutation

Atrial fibrillation (AF) is the most common sustained arrhythmia associated with several cardiac risk factors, but increasing evidences indicated a genetic component. Indeed, genetic variations of the atrial specific KCNA5 gene have been identified in patients with early-onset lone AF. To investigate the molecular mechanisms underlying AF, we reprogrammed to pluripotency polymorphonucleated leukocytes isolated from the blood of a patient carrying a KCNA5 p.D322H mutation, using a commercially available non-integrating system. The generated iPSCs expressed pluripotency markers and differentiated toward cells belonging to the three embryonic germ layers. Moreover, the cells showed a normal karyotype and retained the p.D322H mutation.

Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Disturbances in cardiac potassium conductance are considered as one of the disease mechanisms in AF. We aimed to investigate if mutations in potassium-channel β-subunits KCNE2 and KCNE3 are associated with early-onset lone AF. The coding regions of KCNE2 and KCNE3 were bidirectionally sequenced in 192 unrelated patients diagnosed with early-onset lone AF (<40 years). Two nonsynonymous missense mutations were identified in KCNE2 (M23L and I57T). Both mutations were absent in a healthy control group (n=1500 alleles). Electrophysiological investigations were performed for both mutations in combination with candidate pore-forming α-subunits KV7.1, KV11.1, KV4.3 and KV1.5. A significant gain-of-function effect was observed upon coexpression with KV7.1 and KV7.1+KCNE1. Confocal imaging found no differences in subcellular localization. No disease-suspected mutations were identified in KCNE3. We identified two KCNE2 gain-of-function missense mutations that seem to increase the susceptibility of early-onset lone AF. These results confirm previous findings indicating that gain-of-function in the slow delayed rectifier potassium current might be involved in the pathogenesis of AF.

Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Currently, 14 genes important for ion channel function, intercellular signaling, and homeostatic control have been associated with AF. We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population. Sequencing results of KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5 from 192 early-onset lone AF patients were compared with data from the National Heart, Lung, and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies. Among the lone AF patients, 29 (7.6%) alleles harbored a novel or very rare variant (minor allele frequency <0.1 in the Exome Variant Server), a frequency that was significantly higher than what was found in the reference database (4.1%; with minor allele frequency <0.1; P = .0012). Previously published electrophysiological data showed that 96% (n = 23) of the rare variants that has been functionally investigated (n = 24) displayed significant functional changes. We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population. By presenting these data, we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF.

Genetic Modifier of the QTc Interval Associated With Early-Onset Atrial Fibrillation

BackgroundBoth shortening and prolongation of the QTc interval have been associated with atrial fibrillation (AF). We investigated whether 8 single nucleotide polymorphisms (SNPs) at loci previously shown to affect QTc interval duration were associated with lone AF. MethodsWe included 358 patients diagnosed with lone AF (defined as onset of AF at < 50 years of age in the absence of traditional cardiovascular risk factors) and a control group consisting of 751 individuals free of AF. The 8 loci were genotyped using TaqMan assays. Genotype frequencies in lone AF cases and controls were compared using an additive logistic regression model. ResultsRisk of the development of early-onset lone AF in individuals homozygous for the variant rs2968863 (7q36.1) was higher than in individuals with no copies of the risk allele (odds ratio [OR], 2.40; P = 0.001). The association was also significant after Bonferroni correction (P = 0.016). This polymorphism has been shown to decrease the QTc interval by 1.4 ms in genome-wide association studies (GWAS). The genetic variant is situated close to the long QT syndrome (LQTS) type 2 gene KCNH2 that encodes the potassium channel Kv11.1 (hERG). Sanger sequencing of KCNH2 confirmed the known high linkage disequilibrium between rs2968863 and the nonsynonymous variant K897T in KCNH2. No novel mutations were found in the gene. ConclusionsThe variant rs2968863 (7q36.1), reported in GWAS to shorten the QTc interval, was found to be associated with early-onset lone AF. This may have implications for the pathophysiological understanding of AF.

The PITX2 variant M207V is associated with early-onset lone atrial fibrillation and co-segregates within a family

Purpose: Genetic variants play an important role in lone atrial fibrillation (AF). Ten genetic loci have been associated with AF in genome-wide association (GWA) studies. Variants identified so far can only explain a small proportion of familial clustering, leading to a search for the sources of missing heritability. In all of these studies, the single nucleotide polymorphism (SNP) rs2200733 was the top hit. Recently a meta-analysis of all association studies performed on this SNP confirmed its independent association with AF. It is located upstream of PITX2, a gene important in the cardiogenesis, specifically in the atria, suggesting a potential role in AF. We hypothesized that genetic variants in PITX2 could predispose to early-onset of lone AF. Methods: The coding region of PITX2 was sequenced in 342 cases with early-onset lone AF. 750 controls free of AF were screened for variants identified in the cases. The genotype at the locus rs2200733 was assessed in all cases carrying novel variants in PITX2. Results: Two genetic variants were identified: M207V in four patients, and the previously described A188T in six patients. The frequency of M207V was significantly higher in patients vs. controls (0.58% vs. 0.00%; p=0.01) and in patients vs. the NHLBI Exome Variant Server (0.58% vs. 0.03%; p=0.001), which holds SNP-data on 8,600 European American alleles. M207V co-segregated with both AF and the risk allele of the SNP rs2200733 in one family. All variant-carriers had no mutations in other genes previously associated with AF. Conclusion: This is the first report of 1) an association between a variant in PITX2 and early-onset lone AF, and 2) co-segregation of the SNP rs2200733 with a non-synonymous genetic variant within the coding region of PITX2. This supports the hypothesis of the 4q25 locus being a marker of genetic variation in PITX2 in patients with AF, and suggests that this gene may be involved in AF, independent of major structural abnormalities in the heart.

High frequency of long qt syndrome-associated genetic variants in patients with early-onset lone atrial fibrillation

Background: Atrial fibrillation (AF) is an increasingly common cardiac arrhythmia. Evidence supports that AF has a significant genetic component, and some reports point toward a shared pathophysiology underlying AF and congenital long QT syndrome (LQTS). Purpose: To investigate the frequency of previously published LQTS-associated genetic variants in patients with early-onset lone AF (i.e., AF in the absence of traditional risk factors such as hypertension and ischemic or structural heart disease). Methods and results: We included 210 patients with onset of lone AF before the age of 40 years. Sequencing of all 13 genes so far associated with LQTS revealed 12 patients (6%) carrying a genetic variant previously associated with LQTS. Two LQTS-associated variants were identified in KCNQ1, one in KCNH2, six in SCN5A, one in KCNE2, and two in CAV3. The LQTS-associated variant frequency in the lone AF population was compared to the frequency of LQTS-associated variants in an ethnically matched population represented by recent exome data from the NHLBI GO Exome Sequencing Project (ESP). This comparison revealed that the lone AF patients had a marked overrepresentation of LQTS-associated variants (12 out of 420 alleles, 3.10%) compared with the ESP population (91 out of 6,999 alleles, 1.30%, P = 0.008). Conclusion: We found that patients with early-onset lone AF carry a high frequency of genetic variants previously associated with LQTS. Because such variants may increase the risk of life-threatening arrhythmic events, our finding could have clinical implications for future treatment and risk stratification of lone AF patients.

A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current (Ito) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K(+) Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF. Two hundred and nine unrelated early-onset lone AF patients (<40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group (n = 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of KV4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2. Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early-onset lone AF. This association of KV4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.

Screening of the Ito Regulatory Subunit Klf15 in Patients with Early-Onset Lone Atrial Fibrillation

Several studies have associated mutations in genes encoding potassium channels and accessory subunits involved in cardiac repolarization with increased susceptibility of atrial fibrillation (AF). Recently, the Krüppel-like factor 15 (Klf15) was found to transcriptionally control rhythmic expression of KChIP2, a critical subunit required for generating the transient outward potassium current (Ito), and that deficiency or excess of Klf15 increased the susceptibility of arrhythmias. On this basis we hypothesized that mutations in Klf15 could be associated with AF. A total of 209 unrelated Caucasian lone AF patients were screened for mutations in Klf15 by direct sequencing. No mutations in the lone AF cohort were found. In one patient we found a synonymous variant (c.36C > T). In NHLBI GO Exome Sequencing Project (ESP) the variant was present in 31 of 4269 Caucasian individuals and in 3 of 2200 African Americans. In our cohort Klf15 was not associated with lone AF.

Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation

Genetic factors may be important in the development of atrial fibrillation (AF) in the young. KCNA5 encodes the potassium channel α-subunit KV1.5, which underlies the voltage-gated atrial-specific potassium current IKur. KCNAB2 encodes KVβ2, a β-subunit of KV1.5, which increases IKur. Three studies have identified loss-of-function mutations in KCNA5 in patients with idiopathic AF. We hypothesized that early-onset lone AF is associated with high prevalence of genetic variants in KCNA5 and KCNAB2. The coding sequences of KCNA5 and KCNAB2 were sequenced in 307 patients with mean age of 33 years at the onset of lone AF, and in 216 healthy controls. We identified six novel non-synonymous mutations [E48G, Y155C, A305T (twice), D322H, D469E, and P488S] in KCNA5 in seven patients. None were present in controls. We identified a significantly higher frequency of rare deleterious variants in KCNA5 in the patients than in controls. The mutations were analysed with confocal microscopy and whole-cell patch-clamp techniques. The mutant proteins Y155C, D469E, and P488S displayed decreased surface expression and loss-of-function in patch-clamp studies, whereas E48G, A305T, and D322H showed preserved surface expression and gain-of-function for KV1.5. This study is the first to present gain-of-function mutations in KCNA5 in patients with early-onset lone AF. We identified three gain-of-function and three loss-of-function mutations. We report a high prevalence of variants in KCNA5 in these patients. This supports the hypothesis that both increased and decreased potassium currents enhance AF susceptibility.

Rare Variants in GJA5 Are Associated With Early-Onset Lone Atrial Fibrillation

BackgroundGenetic factors are believed to be important in early-onset lone atrial fibrillation (AF). The gene GJA5 encodes the gap-junction protein Cx40, which together with Cx43 is responsible for the electrical coupling of the atrial cardiomyocytes. The regulatory single nucleotide polymorphism rs10465885 in GJA5 was recently associated with early-onset lone AF (< 60 years) and was also found to be strongly associated with Cx40 messenger RNA levels. We hypothesized that this gene would have a strong effect in patients with a more selected phenotype, and that the findings regarding rs10465885 could be replicated in this group. MethodsThe coding region and flanking intron sequences of GJA5 were resequenced in 342 patients with onset of lone AF before the age of 50 (mean age at onset 34 ± 9 years), and in 216 controls. The single nucleotide polymorphism rs10465885 was genotyped in 342 patients and 534 control subjects and odds ratios were calculated for different genetic models. ResultsGenotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). When resequencing GJA5, we identified the mutation A96S, previously associated with lone AF, which was not present in our control subjects or in any publicly available database or the National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI EVS; 10,758 alleles). ConclusionsWe show a highly significant association between the A allele of rs10465885 and onset of lone AF before age 50. This opposes a previous study, wherein the G allele was found to be associated with AF, and makes it impossible to exclude that the associations are coincidental.

High Prevalence of Long QT Syndrome–Associated SCN5A Variants in Patients With Early-Onset Lone Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The cardiac sodium channel, Na(V)1.5, plays a pivotal role in setting the conduction velocity and the initial depolarization of the cardiac myocytes. We hypothesized that early-onset lone AF was associated with genetic variation in SCN5A. The coding sequence of SCN5A was sequenced in 192 patients with early-onset lone AF. Eight nonsynonymous mutations (T220I, R340Q, T1304M, F1596I, R1626H, D1819N, R1897W, and V1951M) and 2 rare variants (S216L in 2 patients and F2004L) were identified. Of 11 genopositive probands, 6 (3.2% of the total population) had a variant previously associated with long QT syndrome type 3 (LQTS3). The prevalence of LQTS3-associated variants in the patients with lone AF was much higher than expected, compared with the prevalence in recent exome data (minor allele frequency, 1.6% versus 0.3%; P=0.003), mainly representing the general population. The functional effects of the mutations were analyzed by whole cell patch clamp in HEK293 cells; for 5 of the mutations previously associated with LQTS3, patch-clamp experiments showed an increased sustained sodium current, suggesting a mechanistic overlap between LQTS3 and early-onset lone AF. In 9 of 10 identified mutations and rare variants, we observed compromised biophysical properties affecting the transient peak current. In a cohort of patients with early-onset lone AF, we identified a high prevalence of SCN5A mutations previously associated with LQTS3. Functional investigations of the mutations revealed both compromised transient peak current and increased sustained current.

Genetic Loci on Chromosomes 4q25, 7p31, and 12p12 Are Associated With Onset of Lone Atrial Fibrillation Before the Age of 40 Years

BackgroundThree distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 have been associated with atrial fibrillation (AF) in genome-wide association studies (GWAS). Five additional loci have been associated primarily with the PR interval and subsequently with AF. We aimed to investigate if 8 single nucleotide polymorphisms (SNPs), representing the 8 genomic loci previously linked with AF in genome-wide association studies, were associated with early-onset lone AF. MethodsWe included 209 patients with early-onset lone AF, and a control group consisting of 534 individuals free of AF. The 8 SNPs were genotyped using TaqMan assays (Applied Biosystems, Foster City, CA). ResultsThree SNPs were found to be significantly associated with early-onset lone AF: rs2200733 closest to PITX2 (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.16-2.27; P = 0.004), rs3807989 near to CAV1 (OR 1.35; 95% CI, 1.06-1.72; P = 0.015), and rs11047543 near to SOX5 (OR 1.70; 95% CI, 1.18-2.44; P = 0.004). When correcting for multiple testing, rs2200733 and rs11047543 were still significantly associated with AF. ConclusionsThree SNPs, rs2200733 (4q25), rs3807989 (7p31), and rs11047543 (12p12), were associated with early-onset lone AF. All 3 SNPs are positioned close to genes that in previous studies have been demonstrated to be important for cardiac morphology/development, thereby suggesting a link between these SNPs and structural heart disease. Our results however, indicate that variants in these 3 loci are associated with AF through mechanisms that do not involve major structural abnormalities in the heart.

SCN1Bb R214Q found in 3 patients: 1 with Brugada syndrome and 2 with lone atrial fibrillation

SCN1Bb encodes the β-subunit of the sodium channel. A mutation in SCN1Bb R214Q has recently been shown both to increase the Kv4.3 current and to decrease the sodium current. The variant was suggested to increase the susceptibility to Brugada syndrome (BrS). To sequence a population of BrS and early-onset lone atrial fibrillation (AF) patients for the R214Q mutation in the SCN1Bb gene. The coding sequence and splice junctions of SCN1Bb were bidirectionally sequenced by using Big Dye chemistry in 192 early-onset lone AF patients and 22 BrS patients. Three probands carrying the R214Q variant were identified. No mutations were identified in genes previously associated with BrS or AF in these patients. Case 1 also had the onset of persistent lone AF at the age of 39 years. Case 2 was a lone AF case with onset at the age of 39 years and paroxysmal lone AF. Case 3 was a BrS patient with a type 1 electrocardiogram and onset of disease at the age of 54 years. Both lone AF patients had electrocardiograms that raised the suspicion of BrS, but intravenous flecainide testing was, in both cases, negative. R214Q was not present in the control group (n = 216) and has not previously been reported in conjunction to AF. Three patients of 192 young lone AF and 22 BrS patients carried the nonsynonymous R214Q mutations in SCN1Bb, thereby indicating that this variant increases the susceptibility to both BrS and AF.

Letter by Olesen et al Regarding Article, “MOG1: A New Susceptibility Gene for Brugada Syndrome”

To the Editor: In the June issue of Circulation: Cardiovascular Genetics , Kattygnarath and coworkers report MOG1 as a new susceptibility gene for Brugada syndrome (BrS).1 A missense mutation p.E83D was identified in a female patient with aborted sudden cardiac death but not in 281 control subjects. This very interesting finding adds to our understanding of BrS and the (patho-) physiological role of macromolecular complexes underlying the sodium current INa in the heart. Yet, we would like to raise some concerns about this new player in the genetics of BrS. Very recently, we have screened MOG1 in cohorts of BrS and early-onset lone atrial fibrillation.2 In 4 of 209 lone atrial fibrillation cases, we identified a nonsense variation c.181G>T (p. E61X), resulting in premature stop codon …

Response to the Letter by Kattygnarath et al

We want to answer the letter Olesen et al addressed to Circulation: Cardiovascular Genetics after the publication of our report on MOG1 as a new susceptibility gene for Brugada syndrome (BrS). Olesen et al1 screened MOG1 in 23 patients with BrS and in 197 patients with early-onset lone atrial fibrillation, and they identified the nonsense variation c.181G>T (p.E61X) in 4 patients with atrial fibrillation, resulting in a premature stop codon that truncates the protein upstream of the region that interacts with Nav1.5. They also identified this variant in 2 of 488 healthy individuals (ie, in 0.4% of control subjects vs 1.8% of patients). As indicated by Olesen et al, we reported this nonsense variant at the American Heart Association 2009 scientific sessions,2 in an asymptomatic male patient with a type 1 BrS ECG. This variant was thought to be relevant because it had not been found in 100 control individuals. We later found it in 3 other BrS probands, positive or negative for the SCN5A mutation, and in some family members; in addition, we found it in …