The authors regret the errors in the sentence, tables and figures: Page 59, line 9, Statistical analysis The correct sentence is as follows: Categorical variables were compared using the χ2 test or Fisher's exact test. In Table 1, there were several additional characters. The corrected Table 1 is as follows. Table 1Tabled 1MutationFamily no.Patient no.StatusSexAge at onset (y.o.)Age at genetic analysis (y.o.)GenotypeQTc (ms)SymptomTriggers at events Schwartz's scoreL250H1II-1PM−17+446––1II-2FF−6+454––1.52II-1PM−6+475––33II-1PF1321+617SyncopeExercise6I-2FFNA50+451SyncopeNA14II-1PF432+510SyncopeSwimming6V254M5III-1PM78+475SyncopeSwimming5.5II-2FF1039+462VFSwimming5III-3F−4+465––36III-6PF−0+525––3II-2FF−32+505––6II-4F−30+537––4II-8F−19+437––1III-1F77+516SyncopeSwimming6III-3F911+516SyncopeExercise6III-7M−0+482––47II-1PF936+525SyncopeExercise7I-1FMTeenage–NANAS.D.NA–I-2MTeenage–NANAS.D.NA–I-3MTeenage–NANAS.D.NA–I-4MNA62+462SyncopeNA58II-1PM714+436SyncopeExercise29II-2PM−6+459––2I-1FM<1541+413SyncopeExercise3II-1M711+500SyncopeExercise610II-2PM911+537SyncopeSwimming7I-1FM1051+521SyncopeExercise7II-1M6–NANAS.D.Other–II-3M56+455SyncopeExercise7H258P11II-1PF−8+491––412II-1PF−15+491––313II-1PF−15+422––1I-2FF3642+431SyncopeOther3II-2F−13+463––3R259C14II-1PF710+467SyncopeExercise415II-2PF−12+471––3I-1FM−46+438––116II-1PF−8+450––0G269S17II-1PF−9+421––1I-1FM−35+403––118III -1PF−6+484––4.5I -3FM28–NANAS.D.Other-II -3F−31+430––1.5III-2M−7+521––4.519II-1PF−9+454––2I -1FM−33+428––1III -2M−8+416––120II-1PF2121+464VFExercise5I -2FF−50+423––1II -2F1920+400SyncopeOther221II-1PF−9+486––422II-1PF−6+505––423II-2PM−9+486––5I -2FF−45+470––3II-1M−14+443––124II-2PF−6+445––1I -2FF−40+NA–––25II-1PF−14+447––0S277L26III-6PF−28+500––3.5II-2FF32–NANAS.D.NA–III-2F32–NANAS.D.NA–27II-2PF4473+669SyncopeOther5I -2FFNA–NANAS.D.NA–III-3F19–NANAS.D.NA–28II-1PMNA52+600Unknown––29II-4PF<1541+449SyncopeExercise2.5II-1FM<15–NANASyncopeNA–III-1FNA–NANASyncopeNA–30II-1PF−18+468––331II-2PF1134+511SyncopeOther4II-3FF<15–NANASyncopeNA–II-4F3–NANAS.D.NA–32II-1PF1212+508VFSwimming533II-1PF−10+502––334III-2PF−37+459––135II-2PF3634+385TdPOther3I-1FM−62+388––1II-4F−34+436––136III-1PF−11+482––4II-2FF<1545+449SyncopeSwimming– Open table in a new tab P: proband, F: family member, N.A.: not available, (−) at age of onset column: no event, (+) at genotype column: mutation positive, S.D.: sudden death, VF: ventricular fibrillation, TdP: torsade de points, (–) in Schwartz's score column: Schwartz's score was not calculated due to lack of clinical information. In Tables 2a and 2b, we have several mistakes in the numbers. The corrected Tables 2a and 2b are as follows. Table 2aTabled 1C-loopTMMutationL250HV254MH258PR259CG269SS277Lp-Value(n = 6)(n = 23)(n = 5)(n = 4)(n = 20)(n = 22)Female, n (%)4 (67)9 (39)5 (100)3 (75)13 (65)19 (86)0.011Age at genotyping, year22 ± 1720 ± 1817 ± 1319 ± 1820 ± 1535 ± 190.154Heart rate, beats/min61 ± 880 ± 2161 ± 873 ± 1671 ± 1364 ± 140.011QTc, ms492 ± 66486 ± 38460 ± 32457 ± 15451 ± 35486 ± 760.153Symptomatic carrier316113140.001Sudden death, n0400150.449VF/CA, n0100111TdP, n0000010.709Syncope, n31111170.024Triger of symptomSwimming, n1400020.806Exercise, n1701110.081Other, n0110230.064NA, n1400080.289Age of onset arrhythmia≦15 years, n21201070.082>16 years, n001035<0.001Unknown, n1400020.806Schwartz score3.1 ± 2.44.7 ± 1.92.8 ± 1.12.0 ± 1.82.4 ± 1.73.0 ± 1.40.011 Open table in a new tab C-loop: cytoplasmic-loop, TM: transmembrane region, VF: ventricular fibrillation, CA: cardiac arrest, TdP: torsade de points, NA: not available. Values were displayed by mean ± SD or n (%). Differences in characteristics were evaluated using one-way ANOVA or Kruskal–Wallis, χ2 or Fisher's exact test, as appropriate. Table 2bTabled 1C-loopTMMutationL250HV254MH258PR259CG269SS277LP value(n = 6)(n = 19)(n = 5)(n = 4)(n = 19)(n = 14)Female, n (%)4 (67)9 (47)5 (100)3 (75)13 (68)12 (86)0.145Age at genotyping, year22 ± 1721 ± 1819 ± 1319 ± 1820 ± 1535 ± 190.154Heart rate, beats/min61 ± 880 ± 2161 ± 873 ± 1671 ± 1364 ± 140.027QTc, ms492 ± 66486 ± 38460 ± 32457 ± 15451 ± 35486 ± 760.153Symptomatic carrier31211260.13VF/CA, n0100111TdP, n0000010.424Syncope, n31111140.008Triger of symptomSwimming, n1400021Exercise, n1701110.398Other, n0010130.013NA, n1100000.54Age of onset arrhythmia≦15 years, n21101040.034>16 years, n0010220.003Unknown, n1100000.54Schwartz score3.1 ± 2.44.7 ± 1.92.8 ± 1.12.3 ± 2.02.4 ± 1.73.0 ± 1.50.011 Open table in a new tab C-loop: cytoplasmic-loop, TM: transmembrane region, VF: ventricular fibrillation, CA: cardiac arrest, TdP: torsade de points, NA: not available. Values were displayed by mean ± SD or n (%). Differences in characteristics were evaluated using one-way ANOVA or Kruskal–Wallis, χ2 or Fisher's exact test, as appropriate. In Figure 2, the left side of F9, II-2 was filled with orange. In Figure 5, right side of F26, III-6 and left side of F29, III-1 were blank. In Figure 6A, the QTc intervals in V254M was corrected. In Figure 6E, the number of patients >16 y.o. in S277L was corrected. The authors would like to apologise for any inconvenience caused. A challenge for mutation specific risk stratification in long QT syndrome type 1Journal of CardiologyVol. 72Issue 1PreviewLong QT syndrome (LQTS) is an inherited arrhythmic disease associated with prolonged QT interval and fatal arrhythmias such as torsade de pointes (TdP) or ventricular fibrillation (VF) [1]. KCNQ1 is a causative gene of LQTS type 1 (LQT1), which encodes α-subunit of the slow component of delayed rectifier potassium current channel, and its mutations cause the loss of function in IKs [2]. Correlations between mutation sites and phenotypes in LQT1 have been well studied [3,4]. Missense mutations in the C-loop which represented inner linkers between segment 2 and 3 or segment 4 and 5 have been shown to be associated with malignant phenotypes [5]. Full-Text PDF Open Archive

BACKGROUND:The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population.METHODS AND RESULTS:In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of β-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high.CONCLUSIONS:Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.

BACKGROUND:Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease caused by desmosomal gene mutations, and presents as ventricular tachycardia and sudden cardiac death. Although the mean age at onset or diagnosis of ARVC/D are reported to be around the 30-40s, the age-dependent clinical and genetic differences remain unknown.METHODS AND RESULTS:A total of 35 consecutive Japanese probands (23 male) who were clinically diagnosed with ARVC/D were enrolled in the present study, and genetic analysis of PKP2, DSP, DSG2, and DSC2 was done. The mean age at the first symptom and at diagnosis was 38.6±14.8 years and 40.5±17.7 years, respectively. Probands in whom the onset was cardiopulmonary arrest were significantly younger (22.3±15.3 years) than those with arrhythmia (41.1±13.2 years) or congestive heart failure (45.7±8.5 years). On genetic screening, 19 mutation carriers were identified. Although there was no age dependence for each gene mutation carrier, carriers with PKP2 premature stop codon developed the disease at a significantly younger age than other mutation carriers.CONCLUSIONS:The initial clinical manifestations in some young probands were very severe, and PKP2 mutations with a premature stop codon would be associated with disease onset at a younger age.

Background: The relationship between mutation locations in KCNQ1 which is a major gene in long QT syndrome (LQTS) and phenotype has been analyzed and used for risk stratification. Mutations in the transmembrane region (TM) or cytoplasmic-loop (C-loop) are associated with more frequent cardiac events than those in other regions. However, accumulation of LQTS type 1 (LQT1) patients poses the question of whether the location specific risk stratification is really effective. Methods: The study cohort consisted of 67 KCNQ1 mutation carriers and 13 family members who were suspected as having LQTS due to sudden cardiac death or syncope from 36 unrelated families. The KCNQ1 mutations were L250H, V254M, H258P, and R259C located in segment 4-5 linker (C-loop), G269S, and S277L in segment 5 (TM). Results: More than half of the patients with V254M or S277L suffered sudden cardiac death or syncope. In contrast, those with other mutations showed mild phenotype. In these two mutations related to severe phenotype, gender frequency and the age of onset were contrasting, 14 out of 23 patients with V254M were male, 19 out of 22 patients with S277L were female. In the patients we could confirm the age of onset, all of the patients with V254M showed symptoms at less than 15 years old, while 5 out of 12 patients with S277L suffered symptoms after 16 years old. Conclusion: Clinical characteristics were not specific for mutation locations but specific for respective mutations in our LQT1 patients. Patients should be evaluated by their own mutations to prevent severe cardiac events. 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

A 30-year-old Japanese female noticed painful erythematous nodules with ulcers on both legs in 2000. Although the ulcers in the nodules disappeared spontaneously within several months, they recurred repeatedly in 2013 and 2014. She was clinically diagnosed with pyoderma gangrenosum (PG) and treated by a local doctor with oral prednisolone at 15 mg/day, which led to improvement. Leg ulcers recurred again in 2015, and she was therefore referred to our hospital. Physical findings demonstrated many [...]

Congenital long QT syndrome (LQTS) is an important cause of sudden cardiac death in young people without any other structural disease. Mutations in the genes encoding the cardiac ion channels or associated proteins have been shown to result in ion channel dysfunction and thereby causing LQTS. We investigated a Japanese family with LQTS for four generations, with the female family members showing severe symptoms. We performed genetic tests for LQTS-related genes and identified a heterozygous KCNH2 mutation (p.K638del). In the family, the KCNH2 mutation had a very high multigenerational inheritance, and female genotype positives showed more severe phenotypes.

Background: Previous studies of long QT syndrome (LQTS) have revealed the presence of country-specific hot spots in KCNQ1 mutations, and the purpose of this study was to evaluate the influence of a common mutation on clinical phenotypes in Japanese LQT1 patients.Methods and Results: We retrospectively studied the frequency of each mutation in 190 LQT1 Japanese probands and evaluated the clinical severity of LQT1 among carriers with a common mutation. We also compared it with that of carriers with other mutations. In the Japanese cohort, the most common mutation was p. A344spl (c.1032 G> A), comprising a substitution of a guanine for an adenine at the last base of exon 7, and it was found in 17 probands (8.9%). Regarding the clinical characteristics of A344spl carriers, the mean age-of-onset was 10+/-4 years, > 40% were symptomatic, and the mean corrected QT interval was 461+/-30 ms. The prognosis for carriers of the A344spl mutation (n= 31) was intermediate between that for the A341V mutation reported to be associated with severe phenotypes (n= 24) and other mutations (n= 290).Conclusions: The A344spl mutation was a frequent LQTS genotype in Japan, which indicates that the influence of country-specific hot spots should be considered when studying LQT1 clinical phenotypes.

Aims Ryanodine receptor gene (RYR2) mutations are well known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, RYR2 exon 3 deletion has been identified in patients with dilated cardiomyopathy(DCM) and/or CPVT. This study aimed to screen for the RYR2 exon 3 deletion in CPVT probands, characterize its clinical pathology, and confirm the genomic rearrangement.Methods and results Our cohort consisted of 24 CPVT probands. Polymerase chain reaction (PCR)-based conventional genetic analysis did not identify any mutations in coding exons of RYR2 in these probands. They were screened using multiplex ligation-dependent probe amplification (MLPA). In probands identified with RYR2 exon 3 deletion, the precise location of the deletion was identified by quantitative PCR and direct sequencing methods. We identified two CPVT probands from unrelated families who harboured a large deletion including exon 3. The probands were 9- and 17-year-old girls. Both probands had a history of syncope related to emotional stress or exercise, exhibited bradycardia, and were diagnosed with left ventricular non-compaction (LVNC). We examined 10 family members and identified six more RYR2 exon 3 deletion carriers. In total, there were eight carriers, of which seven were diagnosed with LVNC (87.5%). Two carriers under the age of 4 years remained asymptomatic, although they were diagnosed with LVNC. Using quantitative PCR and direct sequencing, we confirmed that the deletions were 1.1 and 37.7 kb in length.Conclusion RYR2 exon 3 deletion is frequently associated with LVNC. Therefore, detection of the deletion offers a new modality for predicting the prognosis of patients with LVNC with ventricular/atrial arrhythmias, particularly in children.

Methods and results CACNA1C gene screening was performed in 278 probands negative for LQTS-related gene mutations. Functional analysis of mutant channels using a whole-cell patch-clamp technique was also performed. Using genetic screening, we identified five novel CACNA1C mutations: P381S, M456I, A582D, R858H, and G1783C in seven (2.5%) unrelated probands. Seven mutation carriers showed alternative clinical phenotypes. Biophysical assay of CACNA1C mutations revealed that the peak calcium currents were significantly larger in R858H mutant channels than those of wild-type (WT). In contrast, A582D mutant channels displayed significantly slower inactivation compared with WT. The two mutant channels exerted different gain-of-function effects on calcium currents.

Rationale: Andersen-Tawil syndrome (ATS) represents ventricular arrhythmia with abnormal U wave, periodic paralysis, and dysmorphysm, resulting from reduction of I K1 current due to KCNJ2 gene mutation. There are few reports about prognosis of ATS. In 2013, a French group reported that the prognosis of ATS was relatively benign under treatment. However, some our KCNJ2 -positive patients show aborted cardiac arrest in their adult phase. Here, we examined long-term outcome in Japanese KCNJ2 -positive ATS cohort. Methods and Results: In 32 probands with at least one of ATS features, we screened KCNJ2, KCNQ1, KCNH2 , and SCN5A genes. Excluding 2 compound mutations and 1 double mutation cases, we found 14 KCNJ2 mutations in 23 probands (71%). We sent the inquiry sheet to all the attending physicians of probands and collected probands’ symptoms, ECGs, and history of cardiac events. For the average follow-up period of 79 months, four of 23 probands (17%) experienced syncope. Twenty-two of 23 (96%) patients showed ventricular arrhythmias, 10 patients (43%) showed periodic pararysis. We compared 23 probands dividing into two groups; one with syncope (n=4), another without syncope (n=19). There are no significant difference in gender, patient number of ventricular arrhythmia, periodic pararysis, and position of KCNJ2 mutations. ECG findings such as HR (61bpm vs. 80 bpm), QTc (439 msec vs. 404 msec), QUc (668 msec vs. 650 msec), and Tpeak-Upeak interval (233 msec vs. 198 msec) showed no significant difference. The age of diagnosis was significantly higher in syncope group (32 ± 9 year old vs. 16 ± 10 year old, P=0.014). Aborted cardiac arrest (n=2, 50% vs. n=0, P=0.0046), beta blocker use (n=4, 100% vs. n=7, 37%, P=0.011) and ICD implantation (n=2, 50% vs. n=0, P=0.0046) were significantly higher in syncope group. Conclusion: We need to watch attentively KCNJ2 positive probands even after childhood.

BACKGROUND:Andersen-Tawil syndrome (ATS) is an autosomal dominant genetic or sporadic disorder characterized by ventricular arrhythmias (VAs), periodic paralyses, and dysmorphic features. The optimal pharmacological treatment of VAs in patients with ATS remains unknown. OBJECTIVE:We evaluated the efficacy and safety of flecainide for VAs in patients with ATS with KCNJ2 mutations. METHODS:Ten ATS probands (7 females; mean age 27 ± 11 years) were enrolled from 6 institutions. All of them had bidirectional VAs in spite of treatment with β-blockers (n = 6), but none of them had either aborted cardiac arrest or family history of sudden cardiac death. Twenty-four-hour Holter recording and treadmill exercise test (TMT) were performed before (baseline) and after oral flecainide therapy (150 ± 46 mg/d). RESULTS:Twenty-four-hour Holter recordings demonstrated that oral flecainide treatment significantly reduced the total number of VAs (from 38,407 ± 19,956 to 11,196 ± 14,773 per day; P = .003) and the number of the longest ventricular salvos (23 ± 19 to 5 ± 5; P = .01). At baseline, TMT induced nonsustained ventricular tachycardia (n = 7) or couplets of premature ventricular complex (n = 2); treatment with flecainide completely (n = 7) or partially (n = 2) suppressed these exercise-induced VAs (P = .008). In contrast, the QRS duration, QT interval, and U-wave amplitude of the electrocardiogram were not altered by flecainide therapy. During a mean follow-up of 23 ± 11 months, no patients developed syncope or cardiac arrest after oral flecainide treatment. CONCLUSION:This multicenter study suggests that oral flecainide therapy is an effective and safe means of suppressing VAs in patients with ATS with KCNJ2 mutations, though the U-wave amplitude remained unchanged by flecainide.

We herein describe two patients with Brugada syndrome in whom J-waves were successfully modified by drugs. Case 1 was a 54-year-old man who presented with repeated ventricular fibrillations (VF) and J-point elevation in the right precordial and lateral leads. After administration of cilostazol (200 mg/d), J-waves disappeared and coved-type ST-segment elevation changed to a saddleback-type for 25 months. Case 2 was a 31-year-old man who presented with a VF storm and J-point elevation in the lateral leads. After administration of quinidine (300 mg/d), J-waves and coved-type ST-segment elevation disappeared for 20 months. J-wave disappearance and coved-type ST-segment elevation were followed by VF suppression, probably due to transient outward potassium current (Ito) suppression.

BACKGROUND  Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation. METHODS AND RESULTS  Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents. CONCLUSIONS  The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block.

Objective:To identify other causative genes for Andersen-Tawil syndrome, which is characterized by a triad of periodic paralysis, cardiac arrhythmia, and dysmorphic features. Andersen-Tawil syndrome is caused in a majority of cases by mutations in KCNJ2, which encodes the Kir2.1 subunit of the inwardly rectifying potassium channel.Methods:The proband exhibited episodic flaccid weakness and a characteristic TU-wave pattern, both suggestive of Andersen-Tawil syndrome, but did not harbor KCNJ2 mutations. We performed exome capture resequencing by restricting the analysis to genes that encode ion channels/associated proteins. The expression of gene products in heart and skeletal muscle tissues was examined by immunoblotting. The functional consequences of the mutation were investigated using a heterologous expression system in Xenopus oocytes, focusing on the interaction with the Kir2.1 subunit.Results:We identified a mutation in the KCNJ5 gene, which encodes the G-protein-activated inwardly rectifying potassium channel 4 (Kir3.4). Immunoblotting demonstrated significant expression of the Kir3.4 protein in human heart and skeletal muscles. The coexpression of Kir2.1 and mutant Kir3.4 in Xenopus oocytes reduced the inwardly rectifying current significantly compared with that observed in the presence of wild-type Kir3.4.Conclusions:We propose that KCNJ5 is a second gene causing Andersen-Tawil syndrome. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.

AIMS:CACNA1C mutations have been reported to cause LQTS type 8 (LQT8; Timothy syndrome), which exhibits severe phenotypes, although the frequency of patients with LQT8 exhibiting only QT prolongation is unknown. This study aimed to elucidate the frequency of CACNA1C mutations in patients with long QT syndrome (LQTS), except those with Timothy syndrome and investigate phenotypic variants.METHODS AND RESULTS:CACNA1C gene screening was performed in 278 probands negative for LQTS-related gene mutations. Functional analysis of mutant channels using a whole-cell patch-clamp technique was also performed. Using genetic screening, we identified five novel CACNA1C mutations: P381S, M456I, A582D, R858H, and G1783C in seven (2.5%) unrelated probands. Seven mutation carriers showed alternative clinical phenotypes. Biophysical assay of CACNA1C mutations revealed that the peak calcium currents were significantly larger in R858H mutant channels than those of wild-type (WT). In contrast, A582D mutant channels displayed significantly slower inactivation compared with WT. The two mutant channels exerted different gain-of-function effects on calcium currents.CONCLUSION:In patients with LQTS, the frequency of CACNA1C mutations was higher than reported. Even without typical phenotypes of Timothy syndrome, CACNA1C mutations may cause QT prolongation and/or fatal arrhythmia attacks.

Channelopathies in Infantile Arrhythmias Background Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades, and postmortem analyses in SIDS victims have provided evidence of this association. However, the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear. Methods and Results Seven infants with potentially lethal arrhythmias at age < 1 year (5 males, age of onset 44.1 ± 72.1 days) were genetically analyzed for KCNQ1, KCNH2, KCNE1–5, KCNJ2, SCN5A , GJA5 , and CALM1 by using denaturing high‐performance liquid chromatography and direct sequencing. Whole‐cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with SCN5A and KCNH2 cDNA. In 5 of 7 patients, we identified 4 mutations (p.N1774D, p.T290fsX53, p.F1486del and p.N406K) in SCN5A , and 1 mutation (p.G628D) in KCNH2 . N1774D, F1486del, and N406K in SCN5A displayed tetrodotoxin‐sensitive persistent late Na + currents. By contrast, SCN5A ‐T290fsX53 was nonfunctional. KCNH2 ‐G628D exhibited loss of channel function. Conclusion Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies. Functional assays revealed both gain and loss of channel function in SCN5A mutations, as well as loss of function associated with the KCNH2 mutation.

BACKGROUND:Mutations in genes encoding the L-type cardiac calcium channel (LTCC) are associated with various types of inherited arrhythmias, including Brugada syndrome (BrS). However, the frequency in Asian populations remains unknown. This study aimed to elucidate disease-causing mutations in LTCC-related genes in Japanese patients diagnosed as BrS or idiopathic ventricular fibrillation (IVF), early repolarization syndrome, short QT syndrome, and compare them with those carrying SCN5A mutations.METHODS AND RESULTS:We screened CACNA1C and CACNB2b in 312 probands and compared the clinical characteristics between probands with gene mutations in CACNA1C or SCN5A. In results, we identified 6 CACNA1C mutations in 7 unrelated probands and SCN5A mutations in 20 probands. There were no CACNB2b mutation carriers. In topology, half of the mutations were located in the C-terminus. Among 7 CACNA1C mutation carriers, 2 were female and 3 were symptomatic; 2 patients were resuscitated from ventricular fibrillation, and 1 patient had syncope. Compared with SCN5A mutation carriers, there were no significant differences in the ECG characteristics. 2 of 3 symptomatic CACNA1C patients were female, but all female SCN5A mutation carriers remained asymptomatic.CONCLUSIONS:We identified 6 CACNA1C mutations in BrS and IVF patients and their phenotypes were varied. Although mutation frequency was not high, screening of LTCC channel genes may be clinically important to prevent unexpected sudden death.

Background: J-point elevation has been demonstrated to be associated with ventricular fibrillation (VF) and has been proposed as a cause of the J-wave syndrome (JWS). A mutation of KCNJ8, S422L, was reported as a culprit gene. This study aimed to determine the prevalence of KCNJ8 mutations in a Japanese population with JWS or idiopathic VF (IVF).Methods: A total of 230 probands with JWS and IVF underwent genetic screening of KCNJ8. To analyze and compare clinical and electrocardiographic characteristics, the probands were divided into 4 groups: Brugada (Br) pattern only, early repolarization (ER) pattern only, Br and ER patterns, and true IVF.Results: The results of the genetic analysis revealed no S422L or other KCNJ8 mutations and indicated no significant difference between the groups.Conclusion: The KCNJ8 mutation showed no association with JWS or IVF among our Japanese patients. (C) 2013 Japanese Heart Rhythm Society. Published by Elsevier B.V. All rights reserved.