Multinational experience with next-generation sequencing: opportunity to identify transthyretin cardiac amyloidosis and Fabry disease.

IF 2.1 3区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular diagnosis and therapy Pub Date : 2024-04-30 Epub Date: 2024-03-18 DOI:10.21037/cdt-23-191
Sandra Marques E Silva, Andrea Virginia Ferreira Chaves, Murillo Antunes, Juan Pablo Costabel, Armando Alves da Fonseca, Adriana Furtado, Juan Esteban Gomez-Mesa, Francisco Javier Marin Gutiérrez, Oren Caspi, Irina Maksimova, Manish Maski, Cecilia Micheletti, José Luiz Barros Pena, Márcia Gonçalves Ribeiro, Maria Juliana Rodríguez-González, Omac Tufekcioglu, Huseyin Onay
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引用次数: 0

Abstract

Background: Sarcomeric hypertrophic cardiomyopathy (HCM) must be differentiated from phenotypically similar conditions because clinical management and prognosis may greatly differ. Patients with unexplained left ventricular hypertrophy require an early, confirmed genetic diagnosis through diagnostic or predictive genetic testing. We tested the feasibility and practicality of the application of a 17-gene next-generation sequencing (NGS) panel to detect the most common genetic causes of HCM and HCM phenocopies, including treatable phenocopies, and report detection rates. Identification of transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD) is essential because of the availability of disease-specific therapy. Early initiation of these treatments may lead to better clinical outcomes.

Methods: In this international, multicenter, cross-sectional pilot study, peripheral dried blood spot samples from patients of cardiology clinics with an unexplained increased left ventricular wall thickness (LVWT) of ≥13 mm in one or more left ventricular myocardial segments (measured by imaging methods) were analyzed at a central laboratory. NGS included the detection of known splice regions and flanking regions of 17 genes using the Illumina NextSeq 500 and NovaSeq 6000 sequencing systems.

Results: Samples for NGS screening were collected between May 2019 and October 2020 at cardiology clinics in Colombia, Brazil, Mexico, Turkey, Israel, and Saudi Arabia. Out of 535 samples, 128 (23.9%) samples tested positive for pathogenic/likely pathogenic genetic variants associated with HCM or HCM phenocopies with double pathogenic/likely pathogenic variants detected in four samples. Among the 132 (24.7%) detected variants, 115 (21.5%) variants were associated with HCM and 17 (3.2%) variants with HCM phenocopies. Variants in MYH7 (n=60, 11.2%) and MYBPC3 (n=41, 7.7%) were the most common HCM variants. The HCM phenocopy variants included variants in the TTR (n=7, 1.3%) and GLA (n=2, 0.4%) genes. The mean (standard deviation) ages of patients with HCM or HCM phenocopy variants, including TTR and GLA variants, were 42.8 (17.9), 54.6 (17.0), and 69.0 (1.4) years, respectively.

Conclusions: The overall diagnostic yield of 24.7% indicates that the screening strategy effectively identified the most common forms of HCM and HCM phenocopies among geographically dispersed patients. The results underscore the importance of including ATTR-CA (TTR variants) and FD (GLA variants), which are treatable disorders, in the differential diagnosis of patients with increased LVWT of unknown etiology.

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下一代测序的多国经验:识别转甲状腺素心脏淀粉样变性和法布里病的机会。
背景:肉瘤型肥厚性心肌病(HCM)必须与表型相似的疾病区分开来,因为临床治疗和预后可能大不相同。原因不明的左心室肥厚患者需要通过诊断性或预测性基因检测及早确诊。我们测试了应用 17 个基因的新一代测序(NGS)面板检测 HCM 和 HCM 表型(包括可治疗的表型)最常见遗传病因的可行性和实用性,并报告了检测率。对转甲状腺素心脏淀粉样变性(ATTR-CA)和法布里病(FD)的鉴定至关重要,因为这两种疾病可进行特异性治疗。及早开始这些治疗可获得更好的临床疗效:在这项国际多中心横断面试验研究中,中心实验室分析了心脏病诊所患者的外周干血斑样本,这些样本中一个或多个左心室心肌节段的左心室壁厚度(LVWT)不明原因地增加了≥13 毫米(通过成像方法测量)。NGS 包括使用 Illumina NextSeq 500 和 NovaSeq 6000 测序系统检测 17 个基因的已知剪接区和侧翼区:NGS 筛查样本于 2019 年 5 月至 2020 年 10 月期间在哥伦比亚、巴西、墨西哥、土耳其、以色列和沙特阿拉伯的心脏病诊所采集。在 535 份样本中,128 份样本(23.9%)检测出与 HCM 或 HCM 表型相关的致病/可能致病基因变异呈阳性,其中 4 份样本检测出双致病/可能致病变异。在检测到的 132 个(24.7%)变异中,115 个(21.5%)变异与 HCM 相关,17 个(3.2%)变异与 HCM 表型相关。MYH7(n=60,11.2%)和MYBPC3(n=41,7.7%)变异是最常见的HCM变异。HCM 表型变异包括 TTR(7 个,1.3%)和 GLA(2 个,0.4%)基因的变异。HCM或HCM表型变异(包括TTR和GLA变异)患者的平均年龄(标准差)分别为42.8(17.9)岁、54.6(17.0)岁和69.0(1.4)岁:24.7% 的总体诊断率表明,筛查策略有效地识别了地理位置分散的患者中最常见的 HCM 和 HCM 表型。结果强调了将 ATTR-CA(TTR 变异)和 FD(GLA 变异)这两种可治疗的疾病纳入病因不明的 LVWT 增高患者的鉴别诊断中的重要性。
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来源期刊
Cardiovascular diagnosis and therapy
Cardiovascular diagnosis and therapy Medicine-Cardiology and Cardiovascular Medicine
CiteScore
4.90
自引率
4.20%
发文量
45
期刊介绍: The journal ''Cardiovascular Diagnosis and Therapy'' (Print ISSN: 2223-3652; Online ISSN: 2223-3660) accepts basic and clinical science submissions related to Cardiovascular Medicine and Surgery. The mission of the journal is the rapid exchange of scientific information between clinicians and scientists worldwide. To reach this goal, the journal will focus on novel media, using a web-based, digital format in addition to traditional print-version. This includes on-line submission, review, publication, and distribution. The digital format will also allow submission of extensive supporting visual material, both images and video. The website www.thecdt.org will serve as the central hub and also allow posting of comments and on-line discussion. The web-site of the journal will be linked to a number of international web-sites (e.g. www.dxy.cn), which will significantly expand the distribution of its contents.
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