Uncovering the gene variants in a global cohort of patients with unexplained increased left ventricular wall thickness using next-generation sequencing
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Genetic analysis using massive parallel sequencing is crucial for the accurate and early diagnosis of hereditary hypertrophic cardiomyopathies and their phenocopies, especially transthyretin cardiac amyloidosis (ATTR-CA) and Fabry disease (FD). This study extends the cardio next-generation sequencing (NGS) pilot study by investigating the detection rate of gene variants causing increased left ventricular wall thickness (LVWT) using an expanded 19-gene NGS panel in a larger global cohort. METHODS: This study included 2068 patients with unexplained increased LVWT enrolled at cardiological clinics across 22 countries/regions between 2020 and 2022. The NGS panel comprised 19 genes associated with hypertrophic cardiomyopathy (HCM) and its phenocopies. Sequencing was performed using the Illumina NextSeq 500 and NovaSeq 6000 systems, with variant interpretation performed according to the American College of Medical Genetics and Genomics guidelines. Novel variants were analyzed using the Human Gene Mutation Database (HGMD®), Franklin, and VarSome. RESULTS: Among the 2068 patients, 453 patients were positive for pathogenic/likely pathogenic variants (21.9%). The diagnostic yield for HCM was 18.4%, while that of HCM phenocopies was 3.5%, including ATTR-CA (1.5%), and FD (0.9%). In patients with a positive test (HCM or HCM phenocopies), the most prevalent HCM-related variants were MYBPC3 and MYH7 (36.4% and 34.4% of all positive samples, respectively), whereas TTR (7.1%) and GLA (4.0%) were the most common phenocopy variants. Other classical phenocopies, Noonan syndrome, Danon disease, and PRKAG2, comprised another 2.0%, 0.9%, and 0.7% of the cohort, respectively. The mean ages for patients with HCM sarcomeric gene variants, HCM phenocopy variants, FD, and ATTR-CA were 45.1 ± 17.6, 50.9 ± 23.7, 51.1 ± 19.4, and 64.6 ± 19.0 years, respectively. CONCLUSION: This study demonstrates the need to include GLA and TTR in NGS panels for patients with increased unexplained LVWT. NGS effectively identifies phenocopies often missed by imaging. Using a large, diverse cohort, this study reveals the prevalence of FD and ATTR-CA in patients with unexplained increased LVWT, reinforcing the importance of NGS for early diagnosis and targeted therapy.
Source: BMC Cardiovascular Disorders
Authors: Michael Arad, Andrea Virginia Ferreira Chaves, Murillo Antunes, Abeer Bakhsh, Kenneth I. Berger, Tse Hung Fat, Armando Alves da Fonseca, Adriana Furtado, Irina Maksimova, Sandra Marques e Silva, Manish Maski, Enrique Monjes, Nelson E. Murillo Benitez, Eduardo Ortuño Campos, Márcia Gonçalves Ribeiro, Maria Juliana Rodriguez-González, Wen-Chung Yu, Huseyin Onay
Institutions: Tel Aviv University, Sheba Medical Center, Centro Universitário Maurício de Nassau, Universidade de São Paulo, Instituto do Coração - HCFMUSP, Universidade São Francisco, King Abdullah Medical City, Sanofi (United States), Queen Mary Hospital, University of Hong Kong, Fleury S.A. (Brazil), Hospital de Base, Sociedade Brasileira de Cardiologia, Vertex Pharmaceuticals (United States), Universidad Santiago de Cali, Hospital Universitario Austral, Universidade Federal do Rio de Janeiro, Institute of Cardiology, National Yang Ming Chiao Tung University, Taipei Veterans General Hospital
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,090
OpenAlex ID: W7154753340