Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center.
Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center.
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DOI：
10.1038/s41436-018-0046-0
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Olivotto I
中科院分区：
文献类型：
--
作者：
Mazzarotto F;Girolami F;Boschi B;Barlocco F;Tomberli A;Baldini K;Coppini R;Tanini I;Bardi S;Contini E;Cecchi F;Pelo E;Cook SA;Cerbai E;Poggesi C;Torricelli F;Walsh R;Olivotto I
肥厚性心肌病（HCM）的基因检测长期依赖于肉瘤基因的Sanger测序。下一代测序（NGS）的出现促进了对其他可疑的hcm致病潜力基因的常规检测。我们利用19年的基因检测结果确定了一组与孟德尔型HCM相关的可靠基因，并评估了扩展的NGS面板的价值。我们分析了1198个单中心HCM先证的基因检测结果，并设计了一个广泛适用的评分，以确定哪些基因在诊断环境中产生有效的结果。与早期仅针对完全验证的肉瘤性HCM基因的筛选相比，扩展的NGS筛选可以迅速识别患有HCM模拟疾病的先证。“诊断有效性”评分强调，除了历史上证实的HCM及其模拟基因外，还应常规筛查PLN。扩展面板在HCM基因检测中的附加价值在于系统筛选与HCM模拟相关的基因，需要不同的患者管理。在临床中，只有一组有限的基因变异具有高度可操作性和可解释性，这表明较大的检测组提供的额外敏感性有限。一个分数估计的相对有效性的一个给定的基因纳入诊断小组提出。
Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels. We dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting. Compared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by “diagnostic effectiveness” highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics. The additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene’s inclusion in diagnostic panels is proposed.
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