University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Department of Genetics, Hanzeplein 1, 9713 GZ Groningen, the Netherlands; University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
Int J Cardiol. 2021 Jun 1;332:99-104. doi: 10.1016/j.ijcard.2021.02.069. Epub 2021 Mar 1.
Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield.
Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs on diagnostic yield.
Patients (N = 2002) referred for clinical genetic analysis underwent diagnostic testing of 55-61 genes associated with cardiomyopathies. Samples were analyzed and evaluated for single nucleotide variants (SNVs), indels and CNVs. CNVs identified in the NGS data and suspected of being pathogenic based on type, size and location were confirmed by additional molecular tests.
A (likely) pathogenic (L)P variant was detected in 22.7% of patients, including 3 with CNVs and 25 where a variant was identified in a gene currently not associated with the patient's cardiomyopathy subtype. Only 15 out of 2002 patients (0.8%) were found to carry two (L)P variants.
The yield of routine clinical diagnostics of cardiomyopathies was relatively low when compared to literature. This is likely due to the fact that our study reports the outcome of patients in daily routine diagnostics, therefore also including patients not fully fulfilling (subtype specific) cardiomyopathy criteria. This may also explain why (L)P variants were identified in genes not associated with the reported subtype. The added value of CNV analysis was shown to be limited but not negligible.
下一代测序（NGS）越来越多地用于心肌病患者的临床评估，因为它可以同时筛查多种与心肌病相关的基因。添加 NGS 数据的拷贝数变异（CNV）分析尚未成为常规，但其可能有助于提高诊断率。
确定我们的靶向 NGS 基因面板在荷兰心肌病患者常规临床诊断中的诊断率，并探讨外显子 CNV 对诊断率的影响。
接受临床遗传分析的患者（N=2002）接受了与心肌病相关的 55-61 个基因的诊断性检测。对样本进行了单核苷酸变异（SNV）、插入缺失（indels）和 CNV 的分析和评估。根据类型、大小和位置，对 NGS 数据中鉴定出的疑似致病性的 CNV 进行了额外的分子检测。
在 22.7%的患者中检测到（可能）致病性（LP）变异，其中包括 3 例携带 CNV 和 25 例在目前与患者心肌病亚型无关的基因中发现变异的患者。在 2002 名患者中，只有 15 名（0.8%）携带两个 LP 变异。
与文献相比，心肌病常规临床诊断的检出率相对较低。这可能是由于我们的研究报告了日常临床诊断中患者的结果，因此也包括不完全符合（亚型特异性）心肌病标准的患者。这也可能解释为什么在未报告的亚型相关基因中发现 LP 变异。CNV 分析的附加值有限，但并非微不足道。
