Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.
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DOI：
10.1371/journal.pone.0181465
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Brugada R
中科院分区：
文献类型：
--
作者：
Mademont-Soler I;Mates J;Yotti R;Espinosa MA;Pérez-Serra A;Fernandez-Avila AI;Coll M;Méndez I;Iglesias A;Del Olmo B;Riuró H;Cuenca S;Allegue C;Campuzano O;Picó F;Ferrer-Costa C;Álvarez P;Castillo S;Garcia-Pavia P;Gonzalez-Lopez E;Padron-Barthe L;Díaz de Bustamante A;Darnaude MT;González-Hevia JI;Brugada J;Fernandez-Aviles F;Brugada R
肥厚型心肌病(HCM)是最常见的遗传性心脏病。下一代测序(NGS)是首选的基因检测方法，但筛查小基因和候选基因的诊断价值以及拷贝数变异(CNV)的作用值得进一步评估。用Sanger测序法(N=84)或NGS测序法(N=30 3)对387例无血缘关系的肥厚型心肌病患者进行了5个最常见基因(MYBPC3、MYH7、TnNT2、TNI3和TPM1)的遗传变异筛查。在NGS队列中，我们分析了另外20个次要或候选基因，并应用了一种专有的生物信息学算法来检测CNV。此外，还比较了427例无结构性心脏病的肥厚性心肌病患者的TTN变异率和分类。主要基因中致病/可能致病(P/LP)变异的患者比例为33.3%，Sanger测序法和NGS队列之间无显著差异。在对另外20个基因的筛查中，12名患者在ACTC1、MYL2、MYL3、TNNC1、GLA和PRKAG2中发现了LP变异。这种方法导致了更多的不确定测试(36.0%vs.9.6%，p<；0.001)，主要是由于TTN中未知意义(VU)的变异。TTN罕见变异的检出率与非结构性心脏病患者组无显著差异。在NGS队列中，4例(1.3%)患者存在致病性CNV：2例MYBPC3缺失，2例PLN全编码区缺失。少数5个主基因无点突变的HCM病例可用副基因或候选基因和CNV的P/LP变异来解释。在肥厚型心肌病患者中筛查TTN基因的变异大大增加了不确定试验的数量，并显示出与非结构性心脏病患者相似的VUS率，这表明不应在肥厚型心肌病中分析该基因的临床用途。
Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation. Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease. The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN. A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM.
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