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
{"title":"Multinational experience with next-generation sequencing: opportunity to identify transthyretin cardiac amyloidosis and Fabry disease.","authors":"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","doi":"10.21037/cdt-23-191","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>MYH7</i> (n=60, 11.2%) and <i>MYBPC3</i> (n=41, 7.7%) were the most common HCM variants. The HCM phenocopy variants included variants in the <i>TTR</i> (n=7, 1.3%) and <i>GLA</i> (n=2, 0.4%) genes. The mean (standard deviation) ages of patients with HCM or HCM phenocopy variants, including <i>TTR</i> and <i>GLA</i> variants, were 42.8 (17.9), 54.6 (17.0), and 69.0 (1.4) years, respectively.</p><p><strong>Conclusions: </strong>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 (<i>TTR</i> variants) and FD (<i>GLA</i> variants), which are treatable disorders, in the differential diagnosis of patients with increased LVWT of unknown etiology.</p>","PeriodicalId":9592,"journal":{"name":"Cardiovascular diagnosis and therapy","volume":"14 2","pages":"294-303"},"PeriodicalIF":2.1000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11070997/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cardiovascular diagnosis and therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21037/cdt-23-191","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/18 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
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.
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.