Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy Impact of Genetics and Revised Task Force Criteria
Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy Impact of Genetics and Revised Task Force Criteria
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DOI：
10.1161/circulationaha.110.976936
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发表时间：
2011-06-14
期刊：
影响因子：
37.8
通讯作者：
McKenna, William J.
中科院分区：
文献类型：
--
作者：
Quarta, Giovanni;Muir, Alison;McKenna, William J.
背景-随着对致心律失常性右室心肌病致病基因的认识，突变分析正在被应用。方法和结果-研究了基因分型在致心律失常性右室心肌病家系评估中的作用，包括已知致病基因突变的发生率，基因分型家系的外显率和表达，以及2010年工作组标准在临床诊断中的应用。对100个家系的210个一级亲属和45个二级亲属进行了临床和分子遗传学评估。在51个家庭中，先证者死亡。在世的先证者有很高的心电图异常(89%)和室性心律失常(78%)的发生率，并有证据表明比亲属更严重的疾病。在58%的家系和73%的在世先证者中发现了明确或可能的因果突变，其中28%具有额外的桥粒变异(即突变或多态)。93名亲属有因果突变；33%符合2010年的标准，而只有19%符合1994年的标准(P=0.03)。另有10%的人发现桥粒基因变异，与发生穿透性疾病的风险增加5倍相关(优势比为4.7；95%可信区间为1.1~20.4；P=0.04)。结论致心律失常性右室心肌病是一种遗传复杂的疾病，具有显著的家族表型多样性。外显率取决于定义，与1994年的标准相比，2010年标准的外显率更大。携带>；1基因变异的亲属发生临床疾病的风险显著增加，这可能是致心律失常性右室心肌病家系表型异质性的一个重要决定因素。(发行量。2011；123：2701-2709。)
Background-With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied.Methods and Results-The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04).Conclusions-Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring > 1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy. (Circulation. 2011;123:2701-2709.)