1376 例 HCM 患者异质队列中基因检测的诊断率。
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.
机构信息
Blueprint Genetics, a Quest Diagnostics Company, 2505 3rd Ave, Suite 204, Seattle, 98121, USA.
Heart and Lung Center, Meilahti Tower Hospital, Helsinki University Hospital, Haartmaninkatu 4, P.O. Box 340, 00029, Helsinki, Finland.
出版信息
BMC Cardiovasc Disord. 2021 Mar 5;21(1):126. doi: 10.1186/s12872-021-01927-5.
BACKGROUND
Genetic testing in hypertrophic cardiomyopathy (HCM) is a published guideline-based recommendation. The diagnostic yield of genetic testing and corresponding HCM-associated genes have been largely documented by single center studies and carefully selected patient cohorts. Our goal was to evaluate the diagnostic yield of genetic testing in a heterogeneous cohort of patients with a clinical suspicion of HCM, referred for genetic testing from multiple centers around the world.
METHODS
A retrospective review of patients with a suspected clinical diagnosis of HCM referred for genetic testing at Blueprint Genetics was undertaken. The analysis included syndromic, myopathic and metabolic etiologies. Genetic test results and variant classifications were extracted from the database. Variants classified as pathogenic (P) or likely pathogenic (LP) were considered diagnostic.
RESULTS
A total of 1376 samples were analyzed. Three hundred and sixty-nine tests were diagnostic (26.8%); 373 P or LP variants were identified. Only one copy number variant was identified. The majority of diagnostic variants involved genes encoding the sarcomere (85.0%) followed by 4.3% of diagnostic variants identified in the RASopathy genes. Two percent of diagnostic variants were in genes associated with a cardiomyopathy other than HCM or an inherited arrhythmia. Clinical variables that increased the likelihood of identifying a diagnostic variant included: an earlier age at diagnosis (p < 0.0001), a higher maximum wall thickness (MWT) (p < 0.0001), a positive family history (p < 0.0001), the absence of hypertension (p = 0.0002), and the presence of an implantable cardioverter-defibrillator (ICD) (p = 0.0004).
CONCLUSION
The diagnostic yield of genetic testing in this heterogeneous cohort of patients with a clinical suspicion of HCM is lower than what has been reported in well-characterized patient cohorts. We report the highest yield of diagnostic variants in the RASopathy genes identified in a laboratory cohort of HCM patients to date. The spectrum of genes implicated in this unselected cohort highlights the importance of pre-and post-test counseling when offering genetic testing to the broad HCM population.
背景
遗传性肥厚型心肌病（HCM）检测是一项已发布的基于指南的推荐。单中心研究和精心挑选的患者队列已经在很大程度上记录了基因检测的诊断率和相应的 HCM 相关基因。我们的目标是评估遗传检测在一个来自世界各地多个中心的具有 HCM 临床疑似的异质患者队列中的诊断率。
方法
对Blueprint Genetics 进行遗传检测的具有疑似临床诊断 HCM 的患者进行回顾性分析。该分析包括综合征、肌病和代谢病因。从数据库中提取基因检测结果和变异分类。将分类为致病性（P）或可能致病性（LP）的变异视为诊断性。
结果
共分析了 1376 个样本。369 个测试具有诊断意义（26.8%）；确定了 373 个 P 或 LP 变异。仅发现一个拷贝数变异。大多数诊断性变异涉及编码肌节的基因（85.0%），其次是 RASopathy 基因中 4.3%的诊断性变异。2%的诊断性变异发生在与肥厚型心肌病或遗传性心律失常以外的心肌病相关的基因中。增加确定诊断性变异可能性的临床变量包括：诊断年龄较早（p<0.0001）、最大壁厚度（MWT）较高（p<0.0001）、阳性家族史（p<0.0001）、无高血压（p=0.0002）和植入式心脏复律除颤器（ICD）（p=0.0004）。
结论
在这个具有 HCM 临床疑似的异质患者队列中，基因检测的诊断率低于在特征明确的患者队列中报告的诊断率。我们报告了迄今为止在 HCM 患者实验室队列中发现的 RASopathy 基因中诊断性变异的最高检出率。在这个未经选择的队列中涉及的基因谱突出了在向广泛的 HCM 人群提供遗传检测时进行预测试和后测试咨询的重要性。
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