Pilichou Kalliopi, Lazzarini Elisabetta, Rigato Ilaria, Celeghin Rudy, De Bortoli Marzia, Perazzolo Marra Marina, Cason Marco, Jongbloed Jan, Calore Martina, Rizzo Stefania, Regazzo Daniela, Poloni Giulia, Iliceto Sabino, Daliento Luciano, Delise Pietro, Corrado Domenico, Van Tintelen J Peter, Thiene Gaetano, Rampazzo Alessandra, Basso Cristina, Bauce Barbara, Lorenzon Alessandra, Occhi Gianluca
From the Departments of Cardiac, Thoracic, and Vascular Sciences (K.P., E.L., I.R., R.C., M.P.M., M.C., S.R., S.I., L.D., D.C., G. T., C.B., B.B.) and Medicine (D.R.), University of Padua, Italy; Department of Biology, University of Padua, Italy (M.D.B., M.C., G.P., A.R., A.L., G.O.); University Medical Center Groningen, University of Groningen, The Netherlands (J.J.); Cardiology Division, Casa di Cura Pederzoli, Peschiera del Garda, Italy (P.D.); and Department of Clinical Genetics, University of Amsterdam, The Netherlands (J.P.V.T.).
Circ Arrhythm Electrophysiol. 2017 Oct;10(10). doi: 10.1161/CIRCEP.117.005324.
Arrhythmogenic cardiomyopathy (AC) is an inherited heart muscle disease associated with point mutations in genes encoding for cardiac desmosome proteins. Conventional mutation screening is positive in ≈50% of probands. Copy number variations (CNVs) have recently been linked to AC pointing to the need to determine the prevalence of CNVs in desmosomal genes and to evaluate disease penetrance by cosegregation analysis in family members.
A total of 160 AC genotype-negative probands for 5 AC desmosomal genes by conventional mutation screening underwent multiplex ligation-dependent probe amplification. Nine heterozygous CNVs were identified in 11 (6.9%) of the 160 probands. Five carried a deletion of the entire plakophilin-2 () gene, 2 a deletion of only exon 4, 1 a deletion of the exons 6 to 11, 1 a duplication of 5' untranslated region till exon 1, 1 the desmocollin-2 () duplication of exons 7 to 9, and 1 a large deletion of chromosome 18 comprising both and genes. All probands were affected by moderate-severe forms of the disease, whereas 10 (32%) of the 31 family members carrying one of these deletions fulfilled the diagnostic criteria.
Genomic rearrangements were detected in ≈7% of AC probands negative for pathogenic point mutations in desmosomal genes, highlighting the potential of CNVs analysis to substantially increase the diagnostic yield of genetic testing. Genotype-phenotype correlation demonstrated the presence of the disease in about one third of family members carrying the CNV, underlying the role of other factors in the development and progression of the disease.
致心律失常性心肌病（AC）是一种遗传性心肌疾病，与编码心脏桥粒蛋白的基因突变有关。传统的突变筛查在约50%的先证者中呈阳性。拷贝数变异（CNV）最近与AC相关，这表明需要确定桥粒基因中CNV的患病率，并通过对家庭成员的共分离分析来评估疾病的外显率。
通过传统突变筛查，对160例5种AC桥粒基因的基因型阴性先证者进行多重连接依赖探针扩增。在160例先证者中的11例（6.9%）中鉴定出9个杂合CNV。5例携带整个桥粒斑菲素蛋白-2（）基因的缺失，2例仅缺失第4外显子，1例缺失第6至11外显子，1例5'非翻译区直至第1外显子的重复，1例桥粒芯胶蛋白-2（）第7至9外显子的重复，1例包含和基因的18号染色体大片段缺失。所有先证者均患有中度至重度疾病，而携带这些缺失之一的31名家庭成员中的10名（32%）符合诊断标准。
在约7%的桥粒基因致病性点突变阴性的AC先证者中检测到基因组重排，突出了CNV分析在大幅提高基因检测诊断率方面的潜力。基因型-表型相关性表明，携带CNV的家庭成员中约有三分之一患有该病，这表明其他因素在疾病的发生和发展中起作用。
