Clinical Features and Outcome of Hypertrophic Cardiomyopathy Associated With Triple Sarcomere Protein Gene Mutations
Clinical Features and Outcome of Hypertrophic Cardiomyopathy Associated With Triple Sarcomere Protein Gene Mutations
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DOI：
10.1016/j.jacc.2009.11.062
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发表时间：
2010-04-06
影响因子：
24
通讯作者：
Olivotto, Iacopo
中科院分区：
文献类型：
--
作者：
Girolami, Francesca;Ho, Carolyn Y.;Olivotto, Iacopo
目的本研究的目的是描述一个大型肥厚型心肌病（HCM）队列中与肌节基因三重突变相关的临床特征。背景在HCM患者中，肌节基因双突变或复合突变杂合性可能与早期发病和更严重的预后相关。三重突变的发生尚未报道。方法通过对8个基因（包括肌球蛋白结合蛋白C（MYBPC 3）、β-肌球蛋白重链（MYH 7）、调节和必需轻链）进行直接脱氧核糖核酸测序，对488名无关指数HCM患者进行肌丝基因突变筛查。结果488例索引患者中，4例患者的肌钙蛋白T（TNT 2）、肌钙蛋白I（TNNI 3）、α-原肌球蛋白（TPM 1）和肌动蛋白（ACTC）均为阳性。（0.8%）携带三重突变，如下：32岁女性中的MYH 7-R869 H、MYBPC 3-E258 K和TNNI 3-A86 fs; 46岁男性中的MYH 7-R723 C、MYH 7-E1455 X和MYBPC 3-E165 D; MYH 7-R869 H、MYBPC 3-K1065 fs和MYBPC 3-P371 R;以及MYH 7-R1079 Q、MYBPC 3-Q969 X和MYBPC 3-R668 H。1例有心脏骤停复苏史，3例有心脏性猝死的显著风险因素，所有患者均需植入植入式心律转复除颤器，2例患者接受适当电击。此外，4例患者中有3例具有严重表型，在40岁时进展为终末期HCM，需要心脏移植（n = 1）或双心室起搏（n = 2）。第四例患者，然而，临床上轻微diseases.ConclusionsHypertrophic心肌病引起的三重肌节基因突变是罕见的，但赋予了一个显着增加的风险终末期进展和室性心律失常，支持多个肌节缺陷和不良后果之间的关联。全面的基因检测可能会提供重要的见解，风险分层，并可能表明需要基于基因型的差异监测策略。（J Am科尔心脏病学杂志2010; 55：1444-53）（C）美国心脏病学会基金会2010年
ObjectivesThe aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort.BackgroundIn patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported.MethodsA total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC).ResultsOf the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n = 1) or biventricular pacing (n = 2). The fourth patient, however, had clinically mild disease.ConclusionsHypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype. (J Am Coll Cardiol 2010; 55: 1444-53) (C) 2010 by the American College of Cardiology Foundation