Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
J Am Coll Cardiol. 2011 Jun 7;57(23):2317-27. doi: 10.1016/j.jacc.2010.12.036.
The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result.
ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test.
Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database.
The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2.
This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation.
本研究旨在确定心律失常性右室心肌病/发育不良（ARVC）基因检测中“背景遗传噪声”的谱和流行率，并确定可指导阳性检测结果解释的遗传关联。
ARVC 是一种潜在致命的遗传性心血管疾病，其特征为心肌细胞丧失和右心室纤维脂肪组织替代。ARVC 易感性基因中的遗传变异尚未得到系统检查，与 ARVC 基因检测相关的背景噪声知之甚少。
使用直接脱氧核糖核酸测序，对荷兰 93 名被诊断为 ARVC 的先证者和来自不同种族的 427 名看似健康的对照者的 PKP2、DSP、DSG2、DSC2 和 TMEM43 的编码外显子/剪接接头进行基因分型。从已发表的报告中获得了另外 82 个 ARVC 病例，并从 ARVD/C 遗传变异数据库中纳入了其他突变。
ARVC 病例的突变总产率为 58%，而对照组为 16%。激进突变在对照组中为 0.5%，而在 ARVC 病例中为 43%，而对照组中错义突变占 16%，与 ARVC 病例相似为 21%。与对照组相比，病例中的突变更频繁地发生在非白种人个体中，定位于 DSP 和 DSG2 的 N 端区域，以及 PKP2 和 DSG2 内高度保守的残基。
这项研究首次全面评估了 ARVC 易感性基因在健康对照中的遗传变异。激进突变是高概率 ARVC 相关突变，而罕见的错义突变应根据种族和民族、突变位置和序列保守性进行解释。
