Prevalence and severity of "Benign" mutations in the β-myosin heavy chain, cardiac troponin T, and α-tropomyosin genes in hypertrophic cardiomyopathy
Prevalence and severity of "Benign" mutations in the β-myosin heavy chain, cardiac troponin T, and α-tropomyosin genes in hypertrophic cardiomyopathy
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DOI：
10.1161/01.cir.0000042675.59901.14
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发表时间：
2002-12-10
期刊：
影响因子：
37.8
通讯作者：
Gersh, BJ
中科院分区：
文献类型：
--
作者：
Van Driest, SL;Ackerman, MJ;Gersh, BJ
背景-基因型-表型相关研究表明，8种特殊突变可导致肥厚型心肌病（HCM）为“良性缺陷”，与接近正常的生存率相关：β-肌球蛋白重链（MYH 7）的N232 S、G256 E、F513 C、V606 M、R719 Q和L908 V;肌钙蛋白T（TNNT 2）的S179 F; α-原肌球蛋白（TPM 1）的D175 N。对HCM患者进行常规基因筛查以检测特定突变，有望提供重要的诊断和预后信息。这些突变的频率和相关的表型在一个大的，HCM的队列是unknown.Methods和Results-A共293无关的HCM患者进行基因分型的良性突变的存在。在知情同意后获得DNA;通过聚合酶链反应扩增特异性MHY 7、TNNT 2和TPM 1片段;通过变性高效液相色谱和自动DNA测序检测突变。293例患者中只有5例（1.7%）具有良性突变。此外，所有5个归因于良性突变的受试者已经表现出临床上严重的HCM表达，所有5个需要手术切除肌，3的5个家族史的心脏性猝死，和1青少年需要原位心脏transplant. Conclusions，这些发现表明罕见的具体。HCM中的突变，并挑战突变特异性临床结果的概念。不到2%的受试者具有良性突变，并且具有良性突变的那些患者经历了非常严重的临床过程。
Background-Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown.Methods and Results-A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and I adolescent requiring an orthotopic heart transplant.Conclusions-These findings demonstrate the rarity of specific. mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course.