{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T22:24:15Z","timestamp":1784672655606,"version":"3.55.0"},"reference-count":78,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T00:00:00Z","timestamp":1730332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Approximately half of hypertrophic cardiomyopathy (HCM) patients lack a precise genetic diagnosis. The likelihood of identifying clinically relevant variants increased over time.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we conducted a gene-centric reanalysis of exome data of 200 HCM cases 5\u2009years after the initial analysis. This reanalysis prioritized genes with a matched HCM entry in the OMIM database and recently emerging HCM-associated genes gathered using a text mining-based literature review. Further classification of the identified genes and variants was performed using the Clinical Genome Resource (ClinGen) resource and American College of Medical Genetics and Genomics (ACMG) guidelines to assess the robustness of gene\u2013disease association and the clinical actionability of the prioritized variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>As expected, the majority of patients carried variants in <jats:italic>MYBPC3<\/jats:italic> and M<jats:italic>YH7<\/jats:italic> genes, 26% (<jats:italic>n<\/jats:italic>\u2009=\u200951) and 8% (<jats:italic>n<\/jats:italic>\u2009=\u200916), respectively, in accordance with the initial analysis. The vast majority of pathogenic (P) and likely pathogenic (LP) variants were found in <jats:italic>MYBPC3<\/jats:italic> (22 out of 40 variants) and <jats:italic>MYH7<\/jats:italic> (8 out of 16 variants) genes. Three genes\u2014not included in the initial analysis\u2014were identified: <jats:italic>SVIL<\/jats:italic>, <jats:italic>FHOD3<\/jats:italic>, and <jats:italic>TRIM63<\/jats:italic>. Considering only patients with unique variants in the last three genes, there was a 9% enhancement in variant identification. Importantly, <jats:italic>SVIL<\/jats:italic> variant carriers presented apical and septal HCM, aortopathies, and severe scoliosis for one patient. Ten patients (5%) carried variants in the <jats:italic>FHOD3<\/jats:italic> gene, six in hotspot regions (exons 12 and 15). We identified seven variants within the <jats:italic>TRIM63<\/jats:italic> gene in 12 patients (6%). Homozygous variants were detected in 2.5% of the cohort in <jats:italic>MYBPC3<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20091), <jats:italic>MYL3<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20091), and <jats:italic>TRIM63<\/jats:italic> (<jats:italic>n<\/jats:italic>\u2009=\u20093) genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study revealed that no variants were found in the <jats:italic>ACTC1<\/jats:italic>, <jats:italic>TPM1<\/jats:italic>, and <jats:italic>TNNI3<\/jats:italic> genes in the HYPERGEN cohort. However, we identified variants in five out of the eight HCM core genes, with a high prevalence in young patients. We identified variants in three recent HCM-associated genes (<jats:italic>SVIL<\/jats:italic>, <jats:italic>FHOD3<\/jats:italic>, and <jats:italic>TRIM63<\/jats:italic>) in 35 patients, with 18 patients carrying unique variants (9%). Our results further emphasize the usefulness of exome data reanalysis, particularly in genotype-negative patients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2024.1480947","type":"journal-article","created":{"date-parts":[[2024,10,31]],"date-time":"2024-10-31T04:51:29Z","timestamp":1730350289000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Exome sequencing data reanalysis of 200 hypertrophic cardiomyopathy patients: the HYPERGEN French cohort 5\u2009years after the initial analysis"],"prefix":"10.3389","volume":"11","author":[{"given":"Hager","family":"Jaouadi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Morel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Martel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lindenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorcan","family":"Lamy de la Chapelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Herbane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9rique","family":"Magdinier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Habib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Jacques","family":"Schott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Zaffran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2227","DOI":"10.1161\/01.CIR.0000066323.15244.54","article-title":"Hypertrophic 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