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1.
目的 研究探索中国人Brugada综合征是否存在基因突变及突变类型。并分析突变可能的致病机制。方法 以SCN5A作为候选基因。应用PCR-SSCP技术对4例患及其家系成员进行突变检测,并用DNA直接测序验证。结果 SSCP分析在一个家系内发现SCN5A基因第8外显子PCR产物出现异常带型,而在200例正常对照中均未发现此改变,DNA直接测序显示SCN5A编码区第317位密码子的第三位碱基G→C的错义突变,并导致位于DⅠS5与DⅠS6节段之间与钠通道蛋白“孔”区相关的第一个P-Loop结构上一个赖氨酸(K)被天冬酰胺(N)取代(K317N)。一个家系调查表明,21例家系成员中共有10例携带,其中有症状(4例)均为携带,2例无症状携带有心电图改变,隐性携带占40%,结论 在中国人中发现了Brugada综合征一个新的SCN5A基因突变。  相似文献   

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Mutations in SCN5A are linked to Brugada syndrome in approximately 20% of all cases (BrS1). Several dozen distinct SCN5A mutations in BrS1 have been associated with the increased risk of cardiac arrhythmias. However, the genotype-phenotype relationship remains elusive. The current study analyzed the SCN5A gene to elucidate the potential variability of clinical features in Japanese BrS1 subjects. Subjects of the present study included 30 probands (25 male subjects, 45 ± 15 years of age) with Brugada-pattern ECG. Seven patients had been resuscitated from cardiopulmonary arrest (CPA group). Another 10 patients had a history of syncope (Sy group), and 13 more remain asymptomatic (Asy group). We identified 8 different SCN5A mutations, including 6 novel mutations (CPA group: 1/7, Sy group: 3/10, Asy group: 4/13). An A735E mutation (located at segment (S)1 in domain (D)2) was identified in the CPA group. A novel splice acceptor site mutation (c.393-1c>t), which may produce a prematurely truncated protein, was identified in the Sy group. An E1784K mutation (C-terminus) and a novel mutation V1951M (C-terminus) were also identified in the Sy group. Four novel missense mutations, A586T (D1-D2 linker), R689H (D1-D2 linker), S1553R (S1-S2 in D4), and Q1706H (S5-Pore in D4) were identified in the Asy group. These data may help us understand the genetic heterogeneity of BrS1, which is more prevalent in Japanese than in whites and other ethnic groups.  相似文献   

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BACKGROUND: Genetic testing in long QT syndrome (LQTS) is moving from research into clinical practice. We have recently piloted a molecular genetics program in a New Zealand research laboratory with a view to establishing a clinical diagnostic service. OBJECTIVE: This study sought to report the spectrum of LQTS and Brugada mutations identified by a pilot LQTS gene testing program in New Zealand. METHODS: Eighty-four consecutive index cases referred for LQT gene testing, from New Zealand and Australia, were evaluated. The coding sequence and splice sites of 5 LQTS genes (KCNQ1, HERG, SCN5A, KCNE1, and KCNE2) were screened for genomic variants by transgenomics denaturing high-performance liquid chromatography (dHPLC) system and automated DNA sequencing. RESULTS: Forty-five LQTS mutations were identified in 43 patients (52% of the cohort): 25 KCNQ1 mutations (9 novel), 13 HERG mutations (7 novel), and 7 SCN5A mutations (2 novel). Forty patients had LQTS, and 3 had Brugada syndrome. Mutations were identified in 14 patients with resuscitated sudden cardiac death: 4 KCNQ1, 5 HERG, 5 SCN5A. In 17 cases there was a family history of sudden cardiac death in a first-degree relative: 8 KCNQ1, 6 HERG, 2 SCN5A, and 1 case with mutations in both KCNQ1 and HERG. CONCLUSION: The spectrum of New Zealand LQTS and Brugada mutations is similar to previous studies. The high proportion of novel mutations (40%) dictates a need to confirm pathogenicity for locally prevalent mutations. Careful screening selection criteria, cellular functional analysis of novel mutations, and development of locally relevant control sample cohorts will all be essential to establishing regional diagnostic services.  相似文献   

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目的研究两个汉族Brugada综合征家系成员相关基因SCN5A外显子的突变情况,探讨相关基因SCN5A外显子在新疆汉、哈、维族健康人群中的单核苷酸多态性(SNP)。方法已明确诊断为Brugada综合征的2位汉族患者及其家系成员共27人作为研究对象,同时纳入246例(汉族75人,哈族68人,维吾尔族103人)健康人群作为对照,采用聚合酶链反应(PCR)进行外显子序列扩增,双脱氧末端中止法进行核酸序列检测,测序结果经核酸序列比对软件(DNAMAN)比对、在线基因序列筛查(http://genome.ucsc.edu/及http://blast.ncbi.nlm.nih.gov/)检测相关基因SCN5A外显子的突变情况,运用统计学软件分析目标基因SNP。结果在2个已明确诊断为Brugada综合征患者SCN5A基因的7号外显子上发现了一个突变位点(T909-),在2个Brugada综合征家系其余7名家族成员中同样发现了该突变位点,健康对照人群中共有29人存在T909-突变。通过比对筛查,T909-突变在SNP数据库中尚没有记录,且T909-在2个Brugada综合征家系及健康汉族人群基因型频率和等位基因频率分布有显著性差异(P〈0.05),在汉族、哈族、维吾尔族健康人群中基因型频率分布及等位基因频率分布无显著性差异(P〉0.05)。结论 T909-可能是Brugada综合征患者SCN5A基因一个新的突变位点,该突变位点多态性在汉族、哈族、维吾尔族健康人群中分布可能无差异。  相似文献   

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BACKGROUND: Risk stratification in Brugada syndrome is controversial, especially in asymptomatic individuals. OBJECTIVE: The purpose of this study was to evaluate tissue Doppler echocardiography in risk stratification of Brugada syndrome. METHODS: Patients with Brugada ECG pattern were enrolled in the study. Left ventricular (LV) preejection period was defined as the time interval between onset of the QRS complex and onset of LV lateral wall systolic wave. Right ventricular (RV) preejection period was defined as the time interval between onset of the QRS complex and onset of RV lateral wall systolic wave. Delay in onset of contraction between RV and LV was defined as RV preejection time - LV preejection time [PET((RV-LV))]. RESULTS: Type 1, 2, and 3 Brugada ECG pattern was found in 30, 56, and 31 patients, respectively. PET((RV-LV)) was significantly greater in type 1 Brugada patients (39.2 +/- 3.2 ms) compared with type 2 (5 +/- 0.3 ms) and 3 (5 +/- 0.4 ms) Brugada patients as well as controls (4.6 +/- 0.3 ms, P <.01 for all comparisons). Among type 1 Brugada patients, PET((RV-LV)) was significantly greater in patients who had previous cardiac events compared with asymptomatic subjects (48.2 +/- 4.3 ms vs 29.5 +/- 3.6 ms, P <.05). In the presence of type 1 Brugada ECG pattern, PET((RV-LV)) > or =40 ms identifies patients likely to have cardiac events, with 85.7% sensitivity and 93.7% specificity. CONCLUSION: PET((RV-LV)) is an important risk indicator for Brugada syndrome.  相似文献   

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The Brugada syndrome describes a subgroup of patients at risk for the occurrence of ventricular fibrillation who have no definable structural heart disease associated with a right bundle branch block conduction pattern and ST-segment elevation in the right precordial leads. This syndrome is caused by genetic defects in the alpha subunit of the sodium channel. This defect causes a reduction in the sodium channel current, which accentuates the epicardial action potential notch leading to ST-segment elevation. Sodium channel blockers can potentiate these findings and screen for patients with intermittent baseline electrocardiographic findings. Because of the poor prognosis of such patients, symptomatic patients should be treated with an implantable cardioverter-defibrillator.  相似文献   

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BACKGROUND: Ventricular fibrillation is one of the leading causes of death in North America. Brugada syndrome is characterized by ST segment elevation on the right precordial leads V1 through V3 and right bundle branch block, and may cause sudden death. Mutations in the SCN5A gene encoding the cardiac voltage-gated Na+ channel (hNav1.5) are associated with Brugada syndrome. OBJECTIVES: In this study, three novel mutations on the SCN5A gene were identified and characterized in different patients with Brugada syndrome. METHODS: Blood samples were collected from patients with Brugada syndrome for gene screening. Mutations found on the SCN5A gene in these patients were reproduced in vitro on hNav1.5 background. Wild type and mutant channels expressed in tsA201 cells were characterized using the patch clamp technique in whole cell configuration and/or confocal microscopy. RESULTS: No current could be recorded from cells expressing the hNav1.5/G1740R mutant, incubated at 37 degrees C. However, at a lower incubation temperature (22 degrees C), macroscopic Na+ currents were recorded. Confocal microscopy study confirmed that at 37 degrees C, hNav1.5/G1740R mutant channels were retained in the endoplasmic reticulum. The E473X and N1774+12X mutants produced truncated proteins and did not express any currents; however, coexpression of each of these mutants with wild type channels shows 50% reduction of Na+ currents. CONCLUSION: This study confirms that the loss of function of cardiac Na+ channels is the basis of the Brugada syndrome clinical phenotype.  相似文献   

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Introduction

Mutations within SCN5A are found in a significant proportion (15–30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions. Genetic testing offers a means to clinically assess and manage affected individuals and their family members.

Methods and results

The proband at age 44?years old exhibited a syncopal event during exercise, and presented later with a spontaneous type-I BrS pattern on 12?lead resting electrocardiogram (ECG). Mutational analysis performed across all SCN5A exons revealed a unique three base-pair deletion p.M741_T742delinsI (c.2223_2225delGAC), in a heterozygous state in the proband and 2 siblings. This mutation was not seen in a cohort of 105 ethnicity-matched controls or in public genome databases. Patch clamp electrophysiology study conducted in TSA201 cells showed an abolishment of sodium current (INa). The proband, and several relatives, also harboured a known SCN5A variant, p.R1193Q (c.3578G>A).

Conclusion

Our study has demonstrated the deleterious effect of a novel SCN5A mutation p.M741_T742delinsI (c.2223_2225delGAC). The findings highlight the complex effects of gender and age in phenotype manifestation. It also offers insights into improving the long-term management of BrS, and the utility of cascade genetic screening for risk stratification.  相似文献   

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Heteroduplex analysis of polymerase chain reaction (PCR)-amplified factor IX (FIX) sequences in eight hemophilia B pedigrees localized the causative hemophilia mutation to a single exon in each case. Subsequent PCR-based direct DNA sequence analysis identified two novel FIX mutations and six recurrent mutations. Three of the eight pedigrees represent sporadic hemophilia B, and direct mutation analysis facilitated hemophilia carrier diagnosis in each case. © 1996 Wiley-Liss, Inc.  相似文献   

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Brugada syndrome: historical perspectives and observations.   总被引:2,自引:0,他引:2  
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Pseudohypoparathyroidism (PHP) refers to two major variants that generally coexist in the same family, PHP type Ia (PHP Ia), in which both PTH resistance and a constellation of physical features, termed Albright's hereditary osteodystrophy (AHO), are present, and pseudopseudohypoparathyroidism (PPHP), in which AHO occurs without PTH resistance. Most patients with PHP Ia show a partial deficiency (50%) of Gs activity, due to loss of function mutations in Gsalpha gene (GNAS1). The present study reports clinical, biochemical, and molecular data of 8 unrelated families with PHP Ia and PPHP. The 13 exons of GNAS1 were screened for mutations by PCR and direct sequencing of the amplified products. We detected heterozygous mutations in the affected members of the 4 families in which PHP Ia was present. In 2 families 2 previously reported deletions in exons 5 and 7 were found, whereas in the other 2 families, 2 novel frameshift deletions were identified in exons 1 and 11, causing a premature stop codon in the mutant allele. No mutation was detected in the families in which PPHP was the only clinical manifestation. In conclusion, we report the first mutational analysis of Italian patients with PHP Ia and PPHP, and we describe two novel deletions in GNAS1. Furthermore, we confirm that these mutations cannot be detected in families with isolated PPHP, suggesting that these forms of AHO are genetically distinct from PHP Ia.  相似文献   

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BACKGROUND: In patients with Brugada syndrome (BS), ventricular fibrillation (VF) occurs mainly during sleep; therefore, not only vagal activity but also bradycardia dependent changes in ECG may relate to the nighttime occurrence of VF. The present study aimed to examine the difference in bradycardia-dependent changes in the ECG of symptomatic and asymptomatic BS patients. METHODS AND RESULTS: Twenty-one patients with BS were categorized into symptomatic (n = 9) and asymptomatic (n = 12) groups. During the electrophysiologic study, the ECG changes were evaluated at RR intervals of 400, 600, 750, 1,000 and 1,100 ms during extrastimulation from the right atrium. The ST levels in V2, and the QT interval in both V2 and V5 were measured. Along with an increase in the RR interval from 400 to 1,100 ms, the ST levels in V2 increased in both groups; the increase did not differ between the 2 groups. In both leads V2 and V5, the prolongation of the QT interval along with an increase in the RR interval from 400 to 1,100 ms was significantly smaller and the QT intervals at an RR interval of 1,100 ms were significantly shorter in the symptomatic than in the asymptomatic group. CONCLUSIONS: In patients with BS, the ST elevation was augmented during bradycardia to a similar extent in both symptomatic and asymptomatic patients. However, a inhibited prolongation of the QT interval during bradycardia was characteristic of symptomatic patients. These unique repolarization dynamics could relate to the nighttime occurrence of VF during bradycardia in patients with BS.  相似文献   

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新胸导联在诊断Brugada综合征中的应用   总被引:8,自引:2,他引:8  
目的 评价自行设计的新胸导联在Brugada综合征诊断中的应用价值。方法 4例Brugada综合征先证者和9例家族成员接受新胸导联和普罗帕酮药物试验。11例无晕厥史和无猝死家族史的房室结折返性室上性心动过速患者作为新胸导联检查对照组。自行设计的心电图新胸导联包括A-G(7)列、0-5(6)行,共42个导联,记录方法同标准胸导联。普罗帕酮试验:普罗帕酮70 mg(体重>70kg者用105 mg)加入生理盐水10 ml于5 min内静脉注射,用药前、后记录标准12导联心电图;用药后标准V1-V3导联J点或ST段抬高超过2 mm(或ST段抬高由BrugadaⅡ或Ⅲ型转变成Ⅰ型),称为药物试验阳性。结果 先证者1~3均有晕厥史,先证者1和3有家族猝死史,先证者2和3晕厥发作时记录到心室颤动,先证者3猝死;除先证者4标准胸导联心电图呈Brugada典型下斜型改变外,先证者1-3标准胸导联心电图不能明确诊断为Brugada综合征。新胸导联发现先证者1-3呈典型Brugada综合征心电图改变,位于标准胸导联以外区域。新胸导联同时发现,5例家族成员在标准胸导联以外区域有典型的Brugada心电图改变。新胸导联阳性者亦被普罗帕酮试验证实。对照组11例新胸导联检查均为阴性。结论 新胸导联有助于发现Brugada综合征典型心电图改变位于标准V1-V3导联以外的病例,且应用安全,方法较简单  相似文献   

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Background and ObjectiveAmong patients with Brugada syndrome (BS) and aborted cardiac arrest, syncope, or inducible ventricular fibrillation at electrophysiologic study (EPS), the only currently recommended therapy is an implantable cardioverter-defibrillator (ICD), but these are not without complications. We assessed the total number of shocks (appropriate and inappropriate) and complications related to ICD in patients with BS.Methods and ResultsTwenty-five patients implanted with ICD for BS in 6 Gulf centers between January 1, 2002, and December 31, 2010, were reviewed. Implantable cardioverter-defibrillator indication was based on aborted cardiac arrest (24%), syncope (56%), or in asymptomatic patients with positive EPS (20%). During a follow-up of 41.2 ± 17.6 months, 3 patients (all with prior cardiac arrest) had appropriate device therapy. Four patients developed complications; 3 of them had inappropriate shocks.ConclusionIn our cohort, appropriate device therapy was limited to cardiac arrest survivors, whereas none of those with syncope and/or positive EPS had arrhythmias. Overall complication rate was relatively high, including inappropriate ICD shocks.  相似文献   

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