{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T23:49:52Z","timestamp":1777765792484,"version":"3.51.4"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T00:00:00Z","timestamp":1704758400000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development","doi-asserted-by":"publisher","award":["10250022110003"],"award-info":[{"award-number":["10250022110003"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institutes of Health Common Fund"},{"name":"Strategic Coordination"},{"DOI":"10.13039\/100000052","name":"Office of the NIH Director","doi-asserted-by":"publisher","award":["U01HG010218"],"award-info":[{"award-number":["U01HG010218"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development","doi-asserted-by":"publisher","award":["91718310"],"award-info":[{"award-number":["91718310"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL83359"],"award-info":[{"award-number":["R01 HL83359"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL149134"],"award-info":[{"award-number":["R01 HL149134"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 122384"],"award-info":[{"award-number":["R01 122384"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development","doi-asserted-by":"publisher","award":["91718310"],"award-info":[{"award-number":["91718310"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development","doi-asserted-by":"publisher","award":["10250022110003"],"award-info":[{"award-number":["10250022110003"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["015.014.036"],"award-info":[{"award-number":["015.014.036"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["1160.18.320"],"award-info":[{"award-number":["1160.18.320"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17\u201325 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA\/Radboudumc at 10\/13.5 (12\/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6\/213 or 3%) with at least four (three AF and one AT) without structural heart disease.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euae003","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T13:16:48Z","timestamp":1704806208000},"source":"Crossref","is-referenced-by-count":8,"title":["Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7950-6140","authenticated-orcid":false,"given":"Sunil K","family":"Vasireddi","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Cardiac Arrhythmia Center, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"},{"name":"Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health , Madison, WI , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-6275","authenticated-orcid":false,"given":"Tanja Zdolsek","family":"Draksler","sequence":"additional","affiliation":[{"name":"Centre for Knowledge Transfer in Information Technologies, Jozef Stefan Institute , Ljubljana , Slovenia"},{"name":"IDefine Europe , Ljubljana , Slovenia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1138-8026","authenticated-orcid":false,"given":"Arianne","family":"Bouman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center , Nijmegen , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4870-0666","authenticated-orcid":false,"given":"Joost","family":"Kummeling","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center , Nijmegen , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-3022","authenticated-orcid":false,"given":"Matthew","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Cardiac Arrhythmia Center, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"},{"name":"Stanford Center for Inherited Cardiovascular Diseases, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"},{"name":"Stanford Center for Undiagnosed Diseases, Falk Cardiovascular Research Center, Stanford University , 870 Quarry Road, Palo Alto, CA 94305 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0429-9922","authenticated-orcid":false,"given":"Chloe","family":"Reuter","sequence":"additional","affiliation":[{"name":"Stanford Center for Inherited Cardiovascular Diseases, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"},{"name":"Stanford Center for Undiagnosed Diseases, Falk Cardiovascular Research Center, Stanford University , 870 Quarry Road, Palo Alto, CA 94305 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7008-1879","authenticated-orcid":false,"given":"Siddharth","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8465-2142","authenticated-orcid":false,"given":"Jacqueline","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurogenetics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions , Baltimore, MD , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1196-1590","authenticated-orcid":false,"given":"Paul G","family":"Fisher","sequence":"additional","affiliation":[{"name":"Department of Neurology, Lucile Packard Children\u2019s Hospital, Stanford University , Stanford, CA , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7552-5053","authenticated-orcid":false,"given":"Sanjiv M","family":"Narayan","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Cardiac Arrhythmia Center, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5467-5877","authenticated-orcid":false,"given":"Paul J","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Cardiac Arrhythmia Center, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3233-6305","authenticated-orcid":false,"given":"Nitish","family":"Badhwar","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Cardiac Arrhythmia Center, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0956-0237","authenticated-orcid":false,"given":"Tjitske","family":"Kleefstra","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center , Nijmegen , The Netherlands"},{"name":"Centre of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry , Venray , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2746-0202","authenticated-orcid":false,"given":"Marco V","family":"Perez","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Cardiac Arrhythmia Center, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"},{"name":"Stanford Center for Inherited Cardiovascular Diseases, Stanford University , 300 Pasteur Drive, Stanford, CA 94305 , USA"},{"name":"Stanford Center for Undiagnosed Diseases, Falk Cardiovascular Research Center, Stanford University , 870 Quarry Road, Palo Alto, CA 94305 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,1,9]]},"reference":[{"key":"2024012220273648000_euae003-B1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1159\/000335648","article-title":"Update on Kleefstra syndrome","volume":"2","author":"Willemsen","year":"2012","journal-title":"Mol Syndromol"},{"key":"2024012220273648000_euae003-B2","first-page":"1993","volume-title":"GeneReviews\u00ae","author":"Kleefstra","year":"2010"},{"key":"2024012220273648000_euae003-B3","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1159\/000494532","article-title":"New insights into Kleefstra syndrome: report of two novel cases with previously unreported features and literature 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Defects Res A Clin Mol Teratol"},{"key":"2024012220273648000_euae003-B10","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1002\/ajmg.a.38852","article-title":"Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome","volume":"176","author":"Okur","year":"2018","journal-title":"Am J Med Genet A"},{"key":"2024012220273648000_euae003-B11","doi-asserted-by":"publisher","first-page":"i15","DOI":"10.1093\/cvr\/cvac066.014","article-title":"The euchromatic histone-lysine N-methyltransferases EHMT1\/2 suppress post-natal cardiomyocyte proliferation via histone 3 lysine 9 (H3K9) demethylation","volume":"118","author":"Chatzieleftheriadis","year":"2022","journal-title":"Cardiovasc Res"},{"key":"2024012220273648000_euae003-B12","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1042\/BST20130012","article-title":"Epigenetics in the heart: the role of histone modifications in cardiac remodelling","volume":"41","author":"Tingare","year":"2013","journal-title":"Biochem Soc Trans"},{"key":"2024012220273648000_euae003-B13","doi-asserted-by":"crossref","first-page":"e1005963","DOI":"10.1371\/journal.pgen.1005963","article-title":"De novo and rare variants at multiple loci support the oligogenic origins of atrioventricular septal heart defects","volume":"12","author":"Priest","year":"2016","journal-title":"PLoS Genet"},{"key":"2024012220273648000_euae003-B14","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1172\/JCI88353","article-title":"The H3K9 dimethyltransferases EHMT1\/2 protect against pathological cardiac hypertrophy","volume":"127","author":"Thienpont","year":"2017","journal-title":"J Clin Invest"},{"key":"2024012220273648000_euae003-B15","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.scr.2016.09.031","article-title":"Establishment of EHMT1 mutant induced pluripotent stem cell (iPSC) line from a 11-year-old Kleefstra syndrome (KS) patient with autism and normal intellectual performance","volume":"17","author":"Varga","year":"2016","journal-title":"Stem Cell Res"},{"key":"2024012220273648000_euae003-B16","doi-asserted-by":"crossref","first-page":"e1179","DOI":"10.1038\/tp.2017.144","article-title":"Altered neurite morphology and cholinergic function of induced pluripotent stem cell-derived neurons from a patient with Kleefstra syndrome and autism","volume":"7","author":"Nagy","year":"2017","journal-title":"Transl Psychiatry"},{"key":"2024012220273648000_euae003-B17","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00702-022-02569-3","article-title":"GenIDA: an international participatory database to gain knowledge on health issues related to genetic forms of neurodevelopmental disorders","volume":"130","author":"Burger","year":"2023","journal-title":"J Neural Transm (Vienna)"},{"key":"2024012220273648000_euae003-B18","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.gene.2016.09.027","article-title":"Targeted next generation sequencing of a panel of autism-related genes identifies an EHMT1 mutation in a Kleefstra syndrome patient with autism and normal intellectual performance","volume":"595","author":"Bock","year":"2016","journal-title":"Gene"},{"key":"2024012220273648000_euae003-B19","first-page":"305","article-title":"The roles of histone lysine methyltransferases in heart development and disease","volume":"10","author":"Zhu","year":"2023","journal-title":"J Cardiovasc Dev Dis"},{"key":"2024012220273648000_euae003-B20","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.3390\/jpm12101680","article-title":"Adipogenic signaling promotes arrhythmia substrates before structural abnormalities in TMEM43 ARVC","volume":"12","author":"Vasireddi","year":"2022","journal-title":"J Pers 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Electrophysiol"}],"container-title":["Europace"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/europace\/advance-article-pdf\/doi\/10.1093\/europace\/euae003\/55284990\/euae003.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/europace\/article-pdf\/26\/1\/euae003\/56323862\/euae003.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/europace\/article-pdf\/26\/1\/euae003\/56323862\/euae003.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T20:59:15Z","timestamp":1705957155000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/europace\/article\/doi\/10.1093\/europace\/euae003\/7513669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,28]]},"references-count":21,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,12,28]]}},"URL":"https:\/\/doi.org\/10.1093\/europace\/euae003","relation":{},"ISSN":["1099-5129","1532-2092"],"issn-type":[{"value":"1099-5129","type":"print"},{"value":"1532-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,1]]},"published":{"date-parts":[[2023,12,28]]},"article-number":"euae003"}}