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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>\u00ae<\/jats:sup>\n                      ), Franklin, and VarSome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>MYBPC3<\/jats:italic>\n                      and\n                      <jats:italic>MYH7<\/jats:italic>\n                      (36.4% and 34.4% of all positive samples, respectively), whereas\n                      <jats:italic>TTR<\/jats:italic>\n                      (7.1%) and\n                      <jats:italic>GLA<\/jats:italic>\n                      (4.0%) were the most common phenocopy variants. Other classical phenocopies, Noonan syndrome, Danon disease, and\n                      <jats:italic>PRKAG2<\/jats:italic>\n                      , 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\u2009\u00b1\u200917.6, 50.9\u2009\u00b1\u200923.7, 51.1\u2009\u00b1\u200919.4, and 64.6\u2009\u00b1\u200919.0 years, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study demonstrates the need to include\n                      <jats:italic>GLA<\/jats:italic>\n                      and\n                      <jats:italic>TTR<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12872-026-05834-5","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T05:56:19Z","timestamp":1776405379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering the gene variants in a global cohort of patients with unexplained increased left ventricular wall thickness using next-generation sequencing"],"prefix":"10.1186","volume":"26","author":[{"given":"Michael","family":"Arad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Virginia Ferreira","family":"Chaves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murillo","family":"Antunes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abeer","family":"Bakhsh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth I.","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tse Hung","family":"Fat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armando","family":"Alves da Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Furtado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Maksimova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Marques e Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manish","family":"Maski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Monjes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson E.","family":"Murillo Benitez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Ortu\u00f1o Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rcia Gon\u00e7alves","family":"Ribeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Juliana","family":"Rodriguez-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chung","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huseyin","family":"Onay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"5834_CR1","doi-asserted-by":"publisher","first-page":"4","DOI":"10.20892\/j.issn.2095-3941.2018.0055","volume":"16","author":"Q Dahui","year":"2019","unstructured":"Dahui Q. 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The study protocol was reviewed and approved by the Institutional Review Board of the Instituto de Puericultura e Pediatria Martag\u00e3o Gesteira, Federal University of Rio de Janeiro (approval no. 5.796.540; CAAE 53630421.3.0000.5264). The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. The authors remain accountable for all aspects of the work, ensuring that any questions related to the accuracy or integrity of any part of the study are appropriately investigated and resolved.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors have completed the ICMJE uniform disclosure form. MA has received modest grant\/research support from Pfizer and Sanofi, as well as speaker honoraria from BMS, Pfizer, and Sanofi. Additionally, the author has received consulting fees from BMS and Sanofi. AVFC has received advisory fees and honoraria for lectures from Takeda, Pint-Pharma, and Sanofi. Additionally, the author has received support for attending meetings and\/or travel from Sanofi, Takeda, and Pint-Pharma. Grant\/research support has been provided by Multicare. AB has received speaker honoraria and grant\/research support. MJRG received speaker honoraria and advisory fees from Sanofi. MAn has received speaker honoraria from Takeda, Pfizer, and Sanofi and grant\/research support from Novartis, Novo Nordisk, Merck Sharp & Dohme, Pfizer, and AstraZeneca. SMeS has received speaker honoraria and grant\/research support from Takeda, Pint Pharma, Pfizer, and Sanofi. The author also received consulting fees from Chiesi Farmaceutici and has attended meetings and travelled with support from Takeda, Pfizer, and Sanofi. AF, IM and KB are employees and shareholders of Sanofi. MM was a former employee of Sanofi who also previously held stock in the company. All authors received support from Sanofi for current research and manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"463"}}