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目的 本研究拟查明1个中国汉族肥厚型心肌病(HCM)家系的致病突变,并探讨基因型-表型关联。方法 利用二代测序技术,全面筛查家系先证者的28个HCM相关致病基因。通过Sanger测序,在家系中验证和筛查发现的可能致病突变,并对突变携带者进行表型分析。结果 二代测序发现先证者携带MYH7基因Glu931del杂合突变。家系筛查发现4名患者均携带该突变,突变与疾病共分离,该突变为此HCM家系的致病突变,常染色体显性遗传。Glu931del突变位于MYH7基因第23外显子,三个核苷酸缺失(c.2791_2793del GAG),导致其所编码的心脏β-肌球蛋白重链的第931位谷氨酸缺失。MYH7基因第931位谷氨酸残基在不同物种间高度保守。临床表型分析发现,家系中4例患者的左心室最厚厚度在19mm-30mm之间,静息状态均无明显左室流出道梗阻,表现为胸痛、心悸和呼吸困难,并伴黑曚或有晕厥史。该家系另有两例患者在家系筛查前发生猝死,确诊年龄分别为5岁和6岁,死亡年龄均为16岁。该家系随访12年,HCM临床症状进展较快,1例患者左心室最大厚度由7mm发展为30mm,两例患者心功能进展为NYHA分级Ⅲ/Ⅳ级。结论 MYH7基因Glu931del突变导致的HCM表型较严重,易发生猝死和心衰,但也存在较大的表型异质性。二代高通量测序可以用于HCM致病基因的全面筛查。 相似文献
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目的研究汉族人群家族性肥厚型心肌病的致病基因突变位点,分析基因型与临床表型的关系。方法采集1个家族性肥厚型心肌病(HCM)家系成员的血液样本,并收集临床表型资料;对该家系先证者的28个HCM相关致病基因利用高通量测序进行靶向重测序;利用Sanger测序在家系成员中检测发现的致病突变位点;分析致病突变携带者的临床表型特点。结果高通量测序和Sanger测序发现并证实先证者携带β肌球蛋白重链基因(MYH7)Val606Met杂合错义突变,该突变在307名正常对照未检出;其他27个HCM相关致病基因中,未检出致病突变。家系遗传筛查发现3例HCM患者均携带MYH7基因Val606Met错义突变,该突变与HCM共分离。该家系3例HCM患者伴有心悸、胸痛、黑矇、晕厥等症状,先证者已经出现严重的心力衰竭,接受心脏移植后上述症状消失,生活质量明显改善。该家系另有2名成员在调查前发生心源性猝死。结论虽然有报道MYH7基因Val606Met错义突变为良性突变,但在本研究家系中,易导致早发心衰和猝死。因突变引起的终末期心衰接受心脏移植可能为最佳的治疗手段。 相似文献
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目的分析携带MYH7基因Arg453Cys突变及TNNT2基因Arg102Trp突变的肥厚型心肌病(hypertrophic cardiomyopathy, HCM)患者的临床表型及预后特点。方法 在接受过全外显子组测序的986例HCM患者中,分析携带上述两个突变的HCM患者的临床表型特点,并通过随访分析预后。结果 在986例HCM患者中发现6例(0.6%)患者携带MYH7基因Arg453Cys突变,患者平均诊断年龄为(24.3±7.5)岁,发病年龄较小;随访过程中5例出现病情进展,其中2例出现心血管死亡。986例HCM患者中发现3例(0.3%)患者携带TNNT2基因Arg102Trp突变,均表现为轻度肥厚,平均左心室最大室壁厚度(left ventricular maximum wall thickness, LVMWT)为(17.33±2.05) mm;2例出现病情恶化,1例因心力衰竭死亡。结论 MYH7基因Arg453Cys突变和TNNT2基因Arg102Trp突变在我国HCM患者中相对常见,虽然携带突变的患者临床表型异质性较大,但发生心血管死亡的风险较高。 相似文献
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目的:比较有MYH7基因突变的肥厚型心肌病(HCM)与扩张型心肌病(DCM患儿的临床特征及基因突变特点,探讨MYH7基因突变对心肌病临床表型的影响。方法:回顾性分析2015年1月至2021年1月,在上海儿童医学中心通过基因检测发现携带MYH7基因突变的30例HCM或DCM患者,收集并分析2组不同心肌病患儿的临床资料与基因突变信息。结果:30例有MYH7基因突变患儿中检出32个突变位点,共26种不同突变位点,其中10种为国内外未报道的突变位点。29个(90.6%)突变位点为错义突变,30个(93.7%)突变位点位于肌球蛋白头颈部。在30例MYH7基因突变患儿中,HCM患儿21例(70%),DCM患儿9例(30%)。2组患儿在性别,诊断年龄,阳性家族史,N末端脑钠肽前体、心肌肌钙蛋白Ⅰ、肌酸激酶同工酶以及血清钙离子水平,心电图异常等方面的差异无统计学意义。结论:不同位点的MYH7基因突变可引起HCM或DCM完全不同的临床表型,在儿童期或疾病早期临床表现无明显差异。 相似文献
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肥厚型心肌病发病机制研究进展 总被引:2,自引:0,他引:2
肥厚型心肌病 ( HCM)是指在无明显阻力及容量负荷增加的情况下 ,心肌发生肥厚 ,临床表现为晕厥、胸闷、胸痛、心律失常、猝死。早在 19世纪末与 2 0世纪初 ,两位病理学家 Liouville H与 Schminche A即对HCM进行了描述 ,直至本世纪中期以来 ,HCM方以其家族聚积倾向 (约 50 %的 FHCM患者有家族史 )、较高病死率及病因不明等特点而倍受基础医学工作者及广大临床医师的重视。1989年 Jarcho等 [1] 首次报道一加拿大家族性肥厚型心肌病 ( familial hypertrophic cardiomyopathy,FHCM)家系 ,致病基因定位于 14号染色体长臂。之后 ,一系列… 相似文献
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目的:利用目标基因靶向捕获高通量测序方法鉴定肥厚型心肌病(hypertrophic cardiomyopathy,HCM)致病突变,并进行基因型-临床表型的分析,以期对临床诊治提供参考依据。方法:连续收集10例HCM患者血液与临床资料。提取全血基因组DNA、文库制备,靶向富集8个编码肌小节蛋白的HCM的致病基因,并行高通量测序。结果:10例患者[平均年龄为(46±7.9)岁,女性占50%]中,4例患者发现5个基因突变位点。双突变(TNNT2 R286H和MYH7 R663H)携带者具有HCM家族史,发病早,左心室重度肥厚,心电图呈现传导阻滞。MYBPC3 D770N和MYBPC3 S236G突变携带者发病年龄晚,左心室肥厚程度较轻。MYH7 R869C突变携带者年龄大,左心室肥厚程度较重,心电图呈现明显左心室肥大证据。结论:对10例HCM患者利用目标基因捕获测序技术筛选出5个致病突变。携带不同突变的患者其临床表型不一致,这对患者的预后和治疗提供了有利的依据。 相似文献
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肥厚型心肌病是指心肌肥厚、显微镜下心肌纤维排列紊乱、心腔缩小、伴或不伴有流出道狭窄的一组心肌疾病。该病除室间隔上部不发生肥厚外,左室其他部位如室间隔下部、左室中部、心室尖、心室后壁以及右室均可发生肥厚。依肥厚情况的不同分为室间隔肥厚型、心尖肥厚型及普通型,各型间临床表现不尽相同。 一、室间隔肥厚型(梗阻型) 临床表现取决于流出道狭窄的程度。患者常有劳累性呼吸困难,2/3患者发生心绞痛、1/3患者发生晕厥,部分病人突然室颤而猝死,病程较长者晚期可发生心力衰竭。但有相当一部分病人病变发展缓慢,虽有一些症状,但病情长期稳定,不影响劳 相似文献
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家族性肥厚型心肌病(familial hypertrophic cardiomyopathy,FHCM)是一种常染色体显性遗传病,肥厚型心肌病临床表现存在很大差异,从无症状到黑朦、晕厥、胸痛、心律失常及心力衰竭等不尽相同,很多青年患者往往平时无症状或首发症状就是猝死。目前,分子遗传学研究已经确定了HCM至少存在13个致病基因。其中,MYH7基因是最常见的致病基因。国内外的研究数据均提示MYH7基因是突变发生率最高的HCM致病基因,在中国黄种人FHCM患者中MYH7基因突变发生率为41%。到目前为止已经发现了超过400种突变可以引起HCM,而位于MYH7基因上的就近200种。因此作为13个已知的致病基因之一,该文对MYH7基因和FHCM的关系作一综述。 相似文献
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心尖肥厚型心肌病是一种原因未明的以心尖部非扩张性肥厚为特征的疾病,其血流动力学改变主要是左室舒张功能减退,导致左室充盈受阻,进而引起左室舒张末期压力升高。1976年,Yamaguchi等首先报告本病,并认为属非梗阻性肥厚型心肌病的亚 相似文献
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Rebeca Lorca Juan Gómez María Martín Rubén Cabanillas Juan Calvo Víctor León Isaac Pascual César Morís Eliecer Coto José Julián R. Reguero 《Revista espa?ola de cardiología》2019,72(2):138-144
Introduction and objectives
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. The current challenge relies on the accurate classification of the pathogenicity of the variants. Transthoracic echocardiography (TTE) is recommended at initial evaluation and cardiac magnetic resonance (CMR) imaging should also be considered. We aimed to reappraise the penetrance and clinical expression of the MYBPC3 p.G263* variant.Methods
Three hundred and eighty-four HCM probands and a control cohort of 450 individuals were studied for the main sarcomere genes by next-generation sequencing. All MYBPC3 p.G263* carriers were identified and family screening was performed. Clinical information was recorded retrospectively before 2015 and prospectively thereafter. Extra effort was invested in performing CMR in all carriers, despite TTE results.Results
Thirteen HCM probands and none of the controls were carriers of the MYBPC3 p.G263* pathogenic variant (according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology). A total of 39 carriers were identified with family screening. Most patients with HCM were asymptomatic at the time of diagnosis and showed late-onset disease. Despite having a relatively benign course in the young, late HCM-related complications could occur. Penetrance was around 70% when evaluated by TTE and was 87.2% with TTE plus CMR. Penetrance was age-dependent, reaching 100% in carriers older than 55 years.Conclusions
MYBPC3 p.G263* shares with most truncating pathogenic variants in this gene a late onset, relatively benign clinical course in the young, and high penetrance. Cardiac magnetic resonance could be a useful tool to evaluate carriers despite TTE results. 相似文献12.
G Purushotham K Madhumohan Mohammad Anwaruddin HA Nagarajaram Vuppaladadhiam Hariram Calambur Narasimhan Murali D Bashyam 《Experimental & Clinical Cardiology》2010,15(1):e1-e4
BACKGROUND:
Familial hypertrophic cardiomyopathy (FHC) is a Mendelian disorder usually caused by mutations in any one of more than 12 genes, most of which encode sarcomere proteins. The disease exhibits extensive genetic heterogeneity, and it is important to identify mutations that result in adverse symptoms and/or lethality in affected individuals. An analysis of disease-causing mutations has been initiated in the Indian population to determine prevalent mutations.METHODS:
FHC was detected using echocardiography and by analysis of clinical symptoms and family history. The disease-causing mutation was identified using polymerase chain reaction DNA sequencing.RESULTS:
The p.R787H mutation was identified in the MYH7 gene in two FHC families. Sequence and structure analysis suggested impaired binding of the mutant protein to the myosin essential light chain.CONCLUSIONS:
Although the mutation results in variable clinical symptoms in the affected individuals, probably owing to the effect of modifier genes and/or environmental factors, it does not appear to be a lethal mutation. 相似文献13.
分析少见类型肥厚型心肌病患者的超声心动图特点 ,提高超声心动图对该病诊断的准确性。利用Acuson12 8XP10彩色电脑声像仪分析了 38例经临床及超声心动图诊断为肥厚型心肌病患者的有关资料 ,采取二维超声心动图多切面、多角度观测室间隔、游离壁厚度和活动幅度以及二尖瓣活动特点 ;M型超声心动图Ⅱa区、Ⅳ区测量房室腔内径及室壁厚度 ;多普勒超声心动图记录左室流出道血流速度、二尖瓣频谱形态及二尖瓣返流速度。 38例肥厚型心肌病患者中 ,以Ⅲ型最为多见 ,占 4 5%。少见类型中心尖肥厚型 2例 ,心尖最厚达 33mm ;后下壁及下间隔肥厚型各 1例 ;对称型肥厚者 2例 ;高血压合并肥厚型心肌病者 2例。肥厚型心肌病的肥厚心肌分布比较复杂 ,少见类型肥厚型心肌病的诊断更应注意多切面、多角度进行探查 ,避免漏诊及误诊。 相似文献
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Martin S. Maron Winnie Xin Katherine B. Sims Rita Butler Tammy S. Haas Ethan J. Rowin Robert J. Desnick Barry J. Maron 《The American journal of medicine》2018,131(2):200.e1-200.e8
Background
Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy.Methods
We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene.Results
In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S, the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy.Conclusions
These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease–affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy. 相似文献15.
The Incremental Value of Magnetic Resonance Imaging for Identification of Apical Pouch in Patients with Apical Variant of Hypertrophic Cardiomyopathy
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Darko Vucicevic M.D. Steven J. Lester M.D. Christopher P. Appleton M.D. Prasad M. Panse M.D. John William Schleifer M.D. Susan Wilansky M.D. 《Echocardiography (Mount Kisco, N.Y.)》2016,33(4):572-578
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目的观察肥厚性心肌病的心电图及动态心电图特点。方法对经超声心动图诊断确诊的88例肥厚性心肌病患者的心电图和动态心电图检查结果进行回顾性分析。结果最常见的心电图和动态心电图异常是ST-T改变,达73.86%~92.05%,其次是左心室肥大,达59.09%。动态心电图显示,肥厚型梗阻性与非梗阻性心肌病的频发室性期前收缩发生率分别为30%与2.g%,多形和成对的室性期前收缩、RonT现象发生率分别为45%与16.2%,短阵室性心动过速速发生率分别为40%与13.2%,两组间差异均有统计学意义(P〈0.05)。结论肥厚型心肌病心电图的主要表现为ST—T改变和左心室肥大,动态心电图有助于室性心律失常的诊断。 相似文献
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目的探讨动态心电图分析系统时域法检测微伏级T波电交替(MTWA)对肥厚型心肌病患者恶性室性心律失常及心脏性猝死的预测价值。方法94例肥厚型心肌病患者(观察组)和105例健康人(对照组)接受24h动态心电图检查并作MTVvA检测,分析两年的死亡、晕厥及恶性心律失常的发生情况。结果对照组MTWA95%正常值参考范围〈36μV。对照组MTWA〉36uV的占10.5%。观察组MTWA〉36uV的占553%。对照组无心血管事件发生;观察组发生恶性心律失常29例,MTWA〉36uV对恶性心律失常诊断的敏感性793%,特异性55.4%;阳性预测值442%,阴性预测值857%。结论MTWA异常的肥厚型心肌病患者发生恶性室性心律失常及心脏性猝死的危险性增加。 相似文献
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Ewa Trzos M.D. Ph.D. Maria Krzemińska–Pakuła M.D. Ph.D. F.E.S.C. Tomasz Rechciński M.D. Ph.D. Karina Wierzbowska–Drabik M.D. Ph.D. Barbara Uznańska M.D. Adam Śmiałowski M.D. Tomasz Rudziński M.D. Ph.D. Małgorzata Kurpesa M.D. Ph.D. 《Annals of noninvasive electrocardiology》2011,16(3):276-286
Background: Nonsustained ventricular tachycardia (nVT) may have ominous implications for patients with hypertrophic cardiomyopathy (HCM). The microvolt T‐wave alternans (TWA) has been proposed as a noninvasive tool‐identifying patients at risk of sudden cardiac death and ventricular tachycardia/fibrillation (VT/VF). The aim of the study was to determine the significance of TWA in predicting nVT episodes and compare how other electrocardiographic parameters can predict the occurrence of nVT. Methods: The study group consisted of 88 patients with HCM. TWA was assessed during exercise test using the CH2000 system. All patients underwent Holter monitoring (HM) within 2–4 weeks before TWA test (preexercise HM1) and immediately after (postexercise HM2). During HM, we analyzed: arrhythmias, QT intervals, the presence of late ventricular potentials (LP), heart rate variability, heart rate turbulence. Results: Depending on TWA results, the patients were divided into two groups: TWA+; 46 patients (52.3%) with positive/indeterminate results, and TWA–; 42 patients (47.7%) with negative results. The nVT episodes were more frequent among TWA(+) both in HM1 and HM2. The presence of TWA increases the risk of postexercise nVT over twenty times (OR = 21.03). Moreover, in HM1, QTc and LP, and in HM2, again QTc and N‐terminal precursor of brain natriuretic peptide proved to be significant predictors of nVT. The addition of TWA to the models did not improve the arrhythmia risk assessment. Conclusions: Repolarization abnormality plays an important role in generating nVT in patients with HCM, but TWA does not specifically predict the risk of arrhythmic end point. Ann Noninvasive Electrocardiol 2011;16(3):276–286 相似文献