Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy
Frequency and clinical expression of cardiac troponin I mutations in 748 consecutive families with hypertrophic cardiomyopathy
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DOI：
10.1016/j.jacc.2004.05.088
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发表时间：
2004-12-21
影响因子：
24
通讯作者：
McKenna, WJ
中科院分区：
文献类型：
--
作者：
Mogensen, J;Murphy, RT;McKenna, WJ
目的 本研究的目的是评估基因诊断在由心肌肌钙蛋白 I (TNNI3) 基因突变引起的肥厚型心肌病 (HCM) 家族临床管理中的潜在效用。 背景 有关 HCM 肌节基因突变的临床疾病表达的知识主要是通过对单个个体（先证者）或选定家庭的调查获得的。为了确定基因诊断在HCM家族中的作用，需要对先证者及其亲属进行系统调查。方法通过直接测序和荧光(F)-SSCP分析对748个连续HCM家族进行心肌肌钙蛋白I研究。邀请具有TNNI3突变的HCM先证者的亲属进行心血管和遗传评估。结果TNNI3突变的患病率为3.1%。突变似乎聚集在外显子 7 和 S 中。在 23 个家族中总共鉴定出 100 个突变携带者，有 13 种不同的突变（其中 6 种是新突变）。疾病外显率为 48%。患者的诊断年龄为20多岁至80多岁。观察到的形态谱代表了多种 HCM。临床上未受影响的突变携带者的两名后代从心脏骤停中复苏，另外四人在初次就诊时突然死亡。六人经历了其他与疾病相关的死亡。 结论 TNNI3 突变的临床表达非常异质，并且在家庭内部和家庭之间存在差异，没有明显的突变或基因特异性疾病模式。数据表明，可以通过定期评估心脏症状和心电图异常来监测疾病的发展。 TNNI3 的基因诊断对于识别具有疾病发展风险的临床上未受影响的突变携带者很有价值，并有助于准确的管理和咨询。 (C) 2004 年由美国心脏病学会基金会资助。
OBJECTIVES The aim of this study was to evaluate the potential utility of genetic diagnosis in clinical management of families with hypertrophic cardiomyopathy (HCM) caused by mutations in the gene for cardiac troponin I (TNNI3).BACKGROUND Knowledge about the clinical disease expression of sarcomeric gene mutations in HCM has predominantly been obtained by investigations of single individuals (probands) or selected families. To establish the role of genetic diagnosis in HCM families, systematic investigations of probands and their relatives are needed.METHODS Cardiac troponin I was investigated by direct sequencing and fluorescent (F)-SSCP analysis in 748 consecutive HCM families. Relatives of HCM probands with TNNI3 mutations were invited for cardiovascular and genetic assessment.RESULTS The prevalence of TNNI3 mutations was 3.1%. Mutations appeared to cluster in exons 7 and S. A total of 100 mutation carriers were identified in 23 families with 13 different mutations (6 novel). Disease penetrance was 48%. Patients were diagnosed from the second to eighth decade of fife. The morphologic spectrum observed represented a wide range of HCM. Two offspring of clinically unaffected mutation carriers were resuscitated from cardiac arrest, and an additional four individuals died suddenly as their initial presentation. Six individuals experienced other disease-related deaths.CONCLUSIONS The clinical expression of TNNI3 mutations was very heterogeneous and varied both within and between families with no apparent mutation- or gene-specific disease pattern. The data suggest that disease development may be monitored by regular assessment of cardiac symptoms and electrocardiographic abnormalities. Genetic diagnosis of TNNI3 is valuable in identifying clinically unaffected mutation carriers at risk of disease development and facilitates accurate management and counseling. (C) 2004 by the American College of Cardiology Foundation.