Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Circulation. 2011 Jun 14;123(23):2690-700. doi: 10.1161/CIRCULATIONAHA.110.988287. Epub 2011 May 23.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce.
One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations).
Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.
致心律失常性右室心肌病（ARVD/C）是一种常染色体显性遗传疾病，具有不完全外显率和可变表达。约 50%的 ARVD/C 指数患者存在编码 5 个桥粒蛋白的基因突变。先前的基因型-表型关系研究主要涉及明显的 ARVD/C 指数患者，因此关于亲属的随访数据很少。
根据 2010 年工作组标准，我们对 149 名 ARVD/C 指数患者（111 名男性患者；年龄 49±13 岁）和 93 个家庭的 302 名亲属（282 名无症状；135 名男性患者；年龄 44±13 岁）进行了临床和基因特征分析。DNA 分析包括桥粒斑蛋白-2（PKP2）、桥粒胶蛋白-2、桥粒芯糖蛋白-2、桥粒斑蛋白和桥粒胶蛋白的测序，以及 PKP2 大片段缺失的多重连接依赖性探针扩增。在 87 名指数患者（58%）中发现了致病性突变，主要为截断 PKP2 突变，包括 3 例存在多种突变。多重连接依赖性探针扩增发现 3 个 PKP2 外显子缺失。在最初无症状的携带突变的亲属中，有 31%被诊断为 ARVD/C，而在最初无症状的指数患者的亲属中，有 5%没有突变。在 V（1）到 V（3）中，尤其是在携带突变的年龄<20 岁的亲属中，观察到延长的终末激活持续时间超过负 T 波。在 45%的筛查家庭中，发现了≥1 名受影响的亲属（90%存在突变）。
致病性桥粒基因突变，主要为截断 PKP2 突变，是荷兰指数患者（58%），甚至是家族性病例（90%）中 ARVD/C 的主要原因。额外的多重连接依赖性探针扩增分析有助于发现 ARVD/C 的致病性突变。在指数患者中发现致病性突变，可使 ARVD/C 诊断风险增加 6 倍的亲属得以识别。在无症状的年轻亲属中，延长的终末激活持续时间似乎是 ARVD/C 的第一个迹象。
