{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:33:27Z","timestamp":1787884407336,"version":"build-2784847793"},"reference-count":67,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2023,12,1]],"date-time":"2023-12-01T00:00:00Z","timestamp":1701388800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16\u2005691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42\u20134.96];\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93\u20132.28];\n                      <jats:italic>P<\/jats:italic>\n                      =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M\n                      <jats:sub>1<\/jats:sub>\n                      : 0.86\u20130.88).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.123.004200","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T05:01:17Z","timestamp":1701147677000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy"],"prefix":"10.1161","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1260-3741","authenticated-orcid":true,"given":"Lara","family":"Curran","sequence":"first","affiliation":[{"name":"National Heart and Lung Institute (L.C., K.A.M., S.L.Z., P.T., R.J.B., C.E.R., A.J.B., A.P., B.P.H., D.J.P., S.K.P., J.S.W.)"},{"name":"Royal Brompton and Harefield Hospitals, Guy\u2019s and St. Thomas\u2019 NHS Foundation Trust (L.C., R.J.B., C.E.R., A.J.B., A.P., B.P.H., D.J.P., S.K.P., J.S.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-5887","authenticated-orcid":true,"given":"Antonio","family":"de Marvao","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (A.d.M., P.I., K.A.M., P.-R.S., A.C., S.L.Z., S.L., M.S., M.J., P.T., R.J.B., S.A.C., J.S.W., D.P.O.)."},{"name":"Department of Women and Children\u2019s Health (A.d.M.)."},{"name":"British Heart Foundation Centre of Research Excellence, School of Cardiovascular &amp; Metabolic Medicine and Sciences, King\u2019s College London, United Kingdom (A.d.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6179-9643","authenticated-orcid":true,"given":"Paolo","family":"Inglese","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (A.d.M., P.I., K.A.M., P.-R.S., A.C., S.L.Z., S.L., M.S., M.J., P.T., R.J.B., S.A.C., J.S.W., D.P.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5445-6906","authenticated-orcid":true,"given":"Kathryn A.","family":"McGurk","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute (L.C., K.A.M., S.L.Z., P.T., R.J.B., C.E.R., A.J.B., A.P., B.P.H., D.J.P., S.K.P., J.S.W.)"},{"name":"Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (A.d.M., P.I., K.A.M., P.-R.S., A.C., S.L.Z., S.L., M.S., M.J., P.T., R.J.B., S.A.C., J.S.W., D.P.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Rapha\u00ebl","family":"Schiratti","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Medical Sciences, Imperial College London, United Kingdom (A.d.M., P.I., K.A.M., P.-R.S., A.C., S.L.Z., S.L., M.S., M.J., P.T., R.J.B., S.A.C., 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