Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia
Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia
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DOI：
10.1016/j.hrthm.2009.09.070
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发表时间：
2010-01-01
期刊：
影响因子：
5.5
通讯作者：
Rampazzo, Alessandra
中科院分区：
文献类型：
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作者：
Bauce, Barbara;Nava, Andrea;Rampazzo, Alessandra
背景：心律失常性右室心肌病/发育不良（ARVC/D）是一种进行性心肌病，在临床表现和预后方面具有广泛的临床谱。目的本研究旨在估计ARVC/D意大利指数队列病例中桥粒蛋白编码基因突变的复合和双杂合子发生率，并评估突变携带者的临床表型。方法采用变性高效液相色谱法（DHPLC）和直接测序技术，对连续42例符合国际工作组诊断标准的ARVC/D指数患者进行PKP2、DSP、DSG2、DSC2和JUP基因突变筛选。结果有猝死家族史的先证者中有3例（7.1%）携带多突变。家庭筛查确定了另外7名多突变携带者。在7例不同基因突变的双杂合子中，2例临床未受影响，2例受影响，3例即使不符合诊断标准也表现出ARVC/D的一些临床体征。同一基因突变的两个复合杂合子和一个携带三种不同突变的受试者显示出一种严重形式的疾病，在年轻时出现心力衰竭。此外，与单突变携带者相比，多突变携带者的左心室受累率更高（P = 0.025）。结论ARVC/D指数病例中复合和双杂合子的发生与突变筛查策略和遗传咨询特别相关。即使多突变携带者在临床表现上表现出广泛的可变性，但与单突变携带者相比，疾病的程度更高。
BACKGROUND Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a progressive cardiomyopathy showing a wide clinical spectrum in terms of clinical expressions and prognoses.OBJECTIVE This study sought to estimate the occurrence of compound and double heterozygotes for mutations in desmosomal proteins encoding genes in a cohort of ARVC/D Italian index cases, and to assess the clinical phenotype of mutations carriers.METHODS Fourty-two consecutive ARVC/D index cases who fulfilled the International Task Force diagnostic criteria were screened for mutations in PKP2, DSP, DSG2, DSC2, and JUP genes by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing.RESULTS Three probands (7.1%) showing a family history of sudden death carried multiple mutations. Family screening identified an additional 7 multiple-mutation carriers. Among the 7 double heterozygotes for mutations in different genes, 2 were clinically unaffected, 2 were affected, and 3 showed some clinical signs of ARVC/D even if they did not fulfill the diagnostic criteria. Two compound heterozygotes for mutations in the same gene and 1 subject carrying 3 different mutations showed a severe form of the disease with heart failure onset at a young age. Moreover, multiple-mutation carriers showed a higher prevalence of left ventricular involvement (P = .025) than single-mutation carriers.CONCLUSION Occurrence of compound and double heterozygotes in ARVC/D index cases is particularly relevant to mutation screening strategy and to genetic counseling. Even if multiple-mutation carriers show a wide variability in clinical expression, the extent of the disease is higher compared to that in single-mutation carriers.