Diagnostic Yield, Interpretation, and Clinical Utility of Mutation Screening of Sarcomere Encoding Genes in Danish Hypertrophic Cardiomyopathy Patients and Relatives
Diagnostic Yield, Interpretation, and Clinical Utility of Mutation Screening of Sarcomere Encoding Genes in Danish Hypertrophic Cardiomyopathy Patients and Relatives
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DOI：
10.1002/humu.20862
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发表时间：
2009-03-01
期刊：
影响因子：
3.9
通讯作者：
Bundgaard, Henning
中科院分区：
文献类型：
--
作者：
Andersen, Paal Skytt;Havndrup, Ole;Bundgaard, Henning
美国心脏协会（ANA）建议进行肥厚型心肌病（HCM）的家庭筛查。我们评估了一个队列的90名丹麦HCM患者和他们的近亲，在所有451人的家庭筛查结合临床评价和肌节基因突变筛查的结果。索引患者筛选10个肌节基因（MYH 7、MYL 3、MYBPC 3、TNNI 3、TNNT 2、TPM 1、ACTC、CSRP 3、TCAP和TNNC 1）的所有编码区和TTN的5个外显子的突变。对亲属进行筛查，以确定是否存在HCM的次要或主要诊断标准，并跟踪DNA变异。共有297名成年亲属（> 18岁）（51.2%）符合HCM的一项或多项标准。在32例索引患者中共检测到38种HCM引起的突变。6名患者携带两种疾病相关突变。仅在本队列中确定了22个突变。家族性HCM的遗传诊断率（53%）几乎是散发性或遗传不清的HCM（19%）的两倍。在具有HCM相关临床事件的额外历史的家庭中，产量最高。在亲属中，29.9%的突变携带者不符合任何临床诊断标准，而在37.5%的没有突变的亲属中，符合一个或打鼾标准。共有60%的家庭成员没有突变，可以放心，停止进一步随访。遗传诊断可在约40%的家族中建立，其中家族性HCM临床事件的产率最高。突变筛查是上级的临床研究，在识别个人没有增加的风险，后续是多余的，但应提供在所有家庭的亲属在发展HCM的风险。《Mutat》30，363-370，2009年。(C)2008 Wiley-Liss，Inc.
The American Heart Association (ANA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (> 18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM-causing mutations were detected in 32 index patients. Six patients carried two disease-associated mutations. Twenty-two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM-related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or snore criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow-up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation-screening was superior to clinical investigation in identification of individuals not at increased risk, where follow-up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 30, 363-370, 2009. (C) 2008 Wiley-Liss, Inc.