Role of genetic analysis in the management of patients with arrhythmogenic right ventricular ysplasia/ardiomyopathy
Role of genetic analysis in the management of patients with arrhythmogenic right ventricular ysplasia/ardiomyopathy
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DOI：
10.1016/j.jacc.2007.08.008
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发表时间：
2007-11-06
影响因子：
24
通讯作者：
McKenna, William J.
中科院分区：
文献类型：
--
作者：
Sen-Chowdhry, Srijita;Syrris, Petros;McKenna, William J.
致心律失常性右心室心肌病（ARVC）是一种公认的心源性猝死的原因，可以通过及时发现和干预来预防。由于相关特征的非特异性、多样的表型表现以及在早期“隐匿”阶段缺乏明显异常，ARVC的临床诊断在索引病例和亲属中都充满了困难。在过去的7年中，研究人员已经分离出桥粒几种成分的致病突变，揭示了疾病的分子机制，并提供了基因检测作为诊断工具的希望。序列分析可能是ARVC基因分型的主要方法，因为ARVC具有显著的等位基因异质性、频繁的“私人”突变和少数人的双基因性，这突出了全面遗传筛查的重要性。在临床实践中实施基因分型的主要技术障碍是对超过40 kb的基因组区域进行序列分析的高昂成本。尽管如此，ARVC基因分型的成功率约为40%，关键的临床应用包括索引病例的确证性检测，以促进边缘调查和家族级联筛查的解释。后者在ARVC中特别有吸引力，因为与年龄相关的疾病需要对大家庭进行终身临床重新评估。目前，遗传分析在诊断中的作用还比较脆弱，但越来越多的早期和家族性疾病个体的鉴定强调了在这一人群中确定风险分层算法的必要性。
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a recognized cause of sudden cardiac death, which may be prevented by timely detection and intervention. Clinical diagnosis of ARVC is fraught with difficulties in both index cases and relatives owing to the nonspecific nature of associated features, diverse phenotypic manifestations, and a lack of conspicuous abnormalities in the early, "concealed" phase. During the past 7 years, researchers have isolated causative mutations in several components of the desmosome, shedding light on the molecular mechanisms underlying the disease and offering the promise of genetic testing as a diagnostic tool. Sequence analysis is likely to be the mainstay of genotyping in ARVC because of marked allelic heterogeneity, frequent "private" mutations, and digenicity in a minority, highlighting the importance of comprehensive genetic screening. The main technical obstacle to implementation of genotyping in clinical practice will be the prohibitive costs of performing sequence analysis of a genomic region exceeding 40 kb. Nevertheless, the success rate of genotyping in ARVC is of the order of 40%, and key clinical applications include confirmatory testing of index cases to facilitate interpretation of borderline investigations and cascade screening of families. The latter is particularly attractive in ARVC, because age-related penetrance otherwise demands lifelong clinical reassessment of extended families. A role for genetic analysis in prognostication is more tenuous at present, but increasing identification of individuals with early and familial disease underscores the need for a definitive risk stratification algorithm in this population.