{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:59:41Z","timestamp":1789070381732,"version":"build-2803163510"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008093","name":"Schulich School of Medicine and Dentistry","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008093","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Michael Smith Foundation"},{"name":"Charles Kerr Distinguished Scholar in Cardiovascular Genetics"},{"name":"University of British Columbia Cardiology Academic Practice Plan"},{"name":"Canadian Cardiovascular Society Atrial Fibrillation Award"},{"name":"Canadian Open Neuroscience Platform Research Scholar Award"},{"name":"GlaxoSmithKline-CIHR Endowed Chair in Genome Sciences"},{"name":"Jacob J. Wolfe Distinguished Medical Research Chair"},{"name":"Edith Schulich Vinet Research Chair in Human Genetics"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Heart and Stroke Foundation of Ontario","award":["G-18-0022147"],"award-info":[{"award-number":["G-18-0022147"]}]},{"name":"Marianne Barrie Philanthropic Fund"},{"DOI":"10.13039\/100004411","name":"Heart and Stroke Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004411","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cardiac Arrhythmia Network of Canada"},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Atrial fibrillation (AF) is a complex heritable disease whose genetic underpinnings remain largely unexplained, though recent work has suggested that the arrhythmia may develop secondary to an underlying atrial cardiomyopathy. We sought to evaluate for enrichment of loss-of-function (LOF) and copy number variants (CNVs) in genes implicated in ventricular cardiomyopathy in \u2018lone\u2019 AF.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Whole-exome sequencing was performed in 255 early onset \u2018lone\u2019 AF cases, defined as arrhythmia onset prior to 60\u2009years of age in the absence of known clinical risk factors. Subsequent evaluations were restricted to 195 cases of European genetic ancestry, as defined by principal component analysis, and focused on a pre-defined set of 43 genes previously implicated in ventricular cardiomyopathy. Bioinformatic analysis identified 6 LOF variants (3.1%), including 3 within the TTN gene, among cases in comparison with 4 of 503 (0.80%) controls [odds ratio: 3.96; 95% confidence interval (CI): 1.11\u201314.2; P\u2009=\u20090.033]. Further, two AF cases possessed a novel heterozygous 8521 base pair TTN deletion, confirmed with Sanger sequencing and breakpoint validation, which was absent from 4958 controls (P\u2009=\u20090.0014). Subsequent cascade screening in two families revealed evidence of co-segregation of a LOF variant with \u2018lone\u2019 AF.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\u2018Lone\u2019 AF cases are enriched in rare LOF variants from cardiomyopathy genes, findings primarily driven by TTN, and a novel TTN deletion, providing additional evidence to implicate atrial cardiomyopathy as an AF genetic sub-phenotype. Our results also highlight that AF may develop in the context of these variants in the absence of a discernable ventricular cardiomyopathy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euaa421","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T20:13:00Z","timestamp":1608667980000},"page":"844-850","source":"Crossref","is-referenced-by-count":27,"title":["Enrichment of loss-of-function and copy number variants in ventricular cardiomyopathy genes in \u2018lone\u2019 atrial fibrillation"],"prefix":"10.1093","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3637-5467","authenticated-orcid":false,"given":"Julieta","family":"Lazarte","sequence":"first","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary W","family":"Laksman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline S","family":"Dron","sequence":"additional","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Leach","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Liew","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam D","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan C","family":"Skanes","sequence":"additional","affiliation":[{"name":"Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorne J","family":"Gula","sequence":"additional","affiliation":[{"name":"Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Leong-Sit","sequence":"additional","affiliation":[{"name":"Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henian","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Trost","sequence":"additional","affiliation":[{"name":"The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen W","family":"Scherer","sequence":"additional","affiliation":[{"name":"The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada"},{"name":"Department of Molecular Genetics, McLaughlin Centre, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2861-5325","authenticated-orcid":false,"given":"Robert A","family":"Hegele","sequence":"additional","affiliation":[{"name":"Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D","family":"Roberts","sequence":"additional","affiliation":[{"name":"Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"2021060815594848900_euaa421-B1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.2147\/CLEP.S47385","article-title":"Epidemiology of atrial fibrillation: European perspective","volume":"6","author":"Zoni-Berisso","year":"2014","journal-title":"Clin Epidemiol"},{"key":"2021060815594848900_euaa421-B2","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1001\/jama.2010.1690","article-title":"Association between familial atrial fibrillation and risk of new-onset atrial fibrillation","volume":"304","author":"Lubitz","year":"2010","journal-title":"JAMA"},{"key":"2021060815594848900_euaa421-B3","doi-asserted-by":"crossref","first-page":"11303","DOI":"10.1038\/ncomms11303","article-title":"A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation","volume":"7","author":"Orr","year":"2016","journal-title":"Nat Commun"},{"key":"2021060815594848900_euaa421-B4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/eurheartj\/ehw379","article-title":"A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation","volume":"38","author":"Gudbjartsson","year":"2017","journal-title":"Eur Heart J"},{"key":"2021060815594848900_euaa421-B5","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1001\/jama.2018.18179","article-title":"Association between titin loss-of-function variants and early-onset atrial fibrillation","volume":"320","author":"Choi","year":"2018","journal-title":"JAMA"},{"key":"2021060815594848900_euaa421-B6","doi-asserted-by":"crossref","first-page":"4316","DOI":"10.1038\/s41467-018-06618-y","article-title":"Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation","volume":"9","author":"Ahlberg","year":"2018","journal-title":"Nat Commun"},{"key":"2021060815594848900_euaa421-B7","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1056\/NEJMoa1505517","article-title":"Shared genetic predisposition in peripartum and dilated cardiomyopathies","volume":"374","author":"Ware","year":"2016","journal-title":"N Engl J Med"},{"key":"2021060815594848900_euaa421-B8","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1038\/s41588-018-0133-9","article-title":"Multi-ethnic genome-wide association study for atrial fibrillation","volume":"50","author":"Roselli","year":"2018","journal-title":"Nat Genet"},{"key":"2021060815594848900_euaa421-B9","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.jacc.2017.06.033","article-title":"Atrial cardiomyopathy: a useful notion in cardiac disease management or a passing fad?","volume":"70","author":"Guichard","year":"2017","journal-title":"J Am Coll Cardiol"},{"key":"2021060815594848900_euaa421-B10","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1093\/europace\/euw161","article-title":"EHRA\/HRS\/APHRS\/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication","volume":"18","author":"Goette","year":"2016","journal-title":"Europace"},{"key":"2021060815594848900_euaa421-B11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"Abecasis","year":"2012","journal-title":"Nature"},{"key":"2021060815594848900_euaa421-B12","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/nn.4524","article-title":"Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder","volume":"20","author":"C Yuen","year":"2017","journal-title":"Nat Neurosci"},{"key":"2021060815594848900_euaa421-B13","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1161\/CIRCULATIONAHA.119.037661","article-title":"Reevaluating the genetic contribution of monogenic dilated cardiomyopathy","volume":"141","author":"Mazzarotto","year":"2020","journal-title":"Circulation"},{"key":"2021060815594848900_euaa421-B14","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ajhg.2017.12.007","article-title":"A comprehensive workflow for read depth-based identification of copy-number variation from whole-genome sequence data","volume":"102","author":"Trost","year":"2018","journal-title":"Am J Hum Genet"},{"key":"2021060815594848900_euaa421-B15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.3389\/fcvm.2020.00011","article-title":"Atrial cardiomyopathy: an unexplored limb of Virchow\u2019s triad for AF stroke prophylaxis","volume":"7","author":"Darlington","year":"2020","journal-title":"Front Cardiovasc Med"},{"key":"2021060815594848900_euaa421-B16","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.jacc.2020.01.013","article-title":"Titin truncating variants in adults without known congestive heart failure","volume":"75","author":"Pirruccello","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"2021060815594848900_euaa421-B17","doi-asserted-by":"crossref","first-page":"10190","DOI":"10.1038\/ncomms10190","article-title":"Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation","volume":"7","author":"Tsai","year":"2016","journal-title":"Nat Commun"},{"key":"2021060815594848900_euaa421-B18","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1038\/nm.2037","article-title":"Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy","volume":"15","author":"Hassel","year":"2009","journal-title":"Nat Med"},{"key":"2021060815594848900_euaa421-B19","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s00431-006-0310-1","article-title":"Succinate dehydrogenase deficiency associated with dilated cardiomyopathy and ventricular noncompaction","volume":"166","author":"Davili","year":"2007","journal-title":"Eur J Pediatr"},{"key":"2021060815594848900_euaa421-B20","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1111\/cge.12169","article-title":"Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of \u03b1B-crystallinopathies","volume":"85","author":"van der Smagt","year":"2014","journal-title":"Clin Genet"}],"container-title":["EP Europace"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/europace\/article-pdf\/23\/6\/844\/38533654\/euaa421.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/europace\/article-pdf\/23\/6\/844\/38533654\/euaa421.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T17:01:24Z","timestamp":1623171684000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/europace\/article\/23\/6\/844\/6157748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,3]]},"references-count":20,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,3,3]]},"published-print":{"date-parts":[[2021,6,7]]}},"URL":"https:\/\/doi.org\/10.1093\/europace\/euaa421","relation":{},"ISSN":["1099-5129","1532-2092"],"issn-type":[{"value":"1099-5129","type":"print"},{"value":"1532-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,6,1]]},"published":{"date-parts":[[2021,3,3]]}}}