{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:57:23Z","timestamp":1790413043221,"version":"4.1.0"},"reference-count":27,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Multiple likely pathogenic\/pathogenic (LP\/P; \u22652) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Of 758 hypertrophic cardiomyopathy probands, we included 382 with \u226545 cardiomyopathy genes screened. There were 224 (59%) with \u22651 rare variant (allele frequency \u22640.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP\/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP\/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP\/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92\u20130.98;\n                      <jats:italic>P<\/jats:italic>\n                      =0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3\u20139.9;\n                      <jats:italic>P<\/jats:italic>\n                      =0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank\n                      <jats:italic>P<\/jats:italic>\n                      =0.008).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>No proband had multiple LP\/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgenetics.116.001666","type":"journal-article","created":{"date-parts":[[2017,8,8]],"date-time":"2017-08-08T20:55:17Z","timestamp":1502225717000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":117,"title":["Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing"],"prefix":"10.1161","volume":"10","author":[{"given":"Charlotte","family":"Burns","sequence":"first","affiliation":[{"name":"From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D.","family":"Bagnall","sequence":"additional","affiliation":[{"name":"From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lien","family":"Lam","sequence":"additional","affiliation":[{"name":"From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Semsarian","sequence":"additional","affiliation":[{"name":"From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jodie","family":"Ingles","sequence":"additional","affiliation":[{"name":"From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (C.B., R.D.B., L.L., C.S., J.I.); Central Clinical School, Sydney Medical School, University of Sydney, New South Wales, Australia (C.B., R.D.B., C.S., J.I.); and Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.B., C.S., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.01.019"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.4.785"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.205"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.05.020"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-014-0099-0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.11.016"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2014.05.009"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000066323.15244.54"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.36.7.542"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.033886"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.07.045"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.4065\/83.6.630"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.755777"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu284"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.06.011"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510687"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.08.036"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.11.062"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.90"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.115.001093"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.144"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08494"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2344"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2712"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw603"}],"container-title":["Circulation: Cardiovascular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGENETICS.116.001666","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T21:34:58Z","timestamp":1715549698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGENETICS.116.001666"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1161\/CIRCGENETICS.116.001666"],"URL":"https:\/\/doi.org\/10.1161\/circgenetics.116.001666","relation":{},"ISSN":["1942-325X","1942-3268"],"issn-type":[{"value":"1942-325X","type":"print"},{"value":"1942-3268","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8]]},"article-number":"e001666"}}