{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:28:11Z","timestamp":1788496091496,"version":"build-2803163510"},"reference-count":128,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007219","name":"Shanghai Natural Science Foundation","doi-asserted-by":"crossref","award":["23ZR1450000"],"award-info":[{"award-number":["23ZR1450000"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: As the most prevalent supraventricular arrhythmia, affecting around 1% of people worldwide, atrial fibrillation (AF) is implicated with a multitude of detrimental clinical sequelae, encompassing congestive failure, thromboembolic cerebral stroke, and premature death. Accumulating epidemiological evidence convincingly demonstrates genetic defects as a cornerstone in the pathogenesis of idiopathic AF. Despite significant genetic underpinnings responsible for AF, owing to substantial genetic heterogeneity, the predisposing genetic substrates for AF in most individuals remain to be ascertained. Methods: A four-generation pedigree suffering from familial AF and a cohort of 238 subjects affected with idiopathic AF, together with 266 healthy people, were enrolled prospectively. Pan-exome sequencing analysis was implemented on the chosen AF pedigree members, and Sanger sequencing assay was performed on all research subjects. The functional effects of the detected HAND2 variations were examined via an in vitro dual-reporter gene measurement. Results: Two novel heterozygous truncating HAND2 variations, NM_021973.3: c.138G&gt;A; p.(Trp46*) and NM_021973.3: c.337C&gt;T; p.(Gln113*), were discovered in the AF pedigree and one of the 238 AF cases, respectively. The two HAND2 variants co-segregated with the AF phenotype and were absent from the 532 control chromosomes of 266 healthy individuals. Quantitative reporter gene assays unveiled that both Trp46*- and Gln113*-mutant HAND2 failed to transcriptionally activate HCN4 and NPPA, two AF-causative genes. Additionally, the two variations nullified the synergistic transcriptional activation of NPPA by HAND2 and GATA4, another recognized gene predisposing to AF. Conclusions: These findings support HAND2 as a strong candidate gene contributing to AF susceptibility, which unravels novel etiopathogenesis underpinning the occurrence and perpetuation of AF and offers a potential molecular target for individualized medicine.<\/jats:p>","DOI":"10.3390\/genes17060701","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T10:19:53Z","timestamp":1781691593000},"page":"701","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rare Truncating HAND2 Variants Predispose to Atrial Fibrillation"],"prefix":"10.3390","volume":"17","author":[{"given":"Hong","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Qing","family":"Hu","sequence":"additional","affiliation":[{"name":"General Practice of Western Medicine, Community Health Service Center of Gonghexin Road Sub-District, Jing\u2019an District, Shanghai 200072, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao-Liang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cardiac Arrhythmia Center, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-Biao","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Xi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Fifth People\u2032s Hospital, Fudan University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Jia","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Huashan Hospital, Fudan University, Shanghai 200040, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0291-8395","authenticated-orcid":false,"given":"Yi-Qing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Fifth People\u2032s Hospital, Fudan University, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1161\/CIR.0000000000001193","article-title":"2023 ACC\/AHA\/ACCP\/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"149","author":"Joglar","year":"2024","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100785","DOI":"10.1016\/j.lanepe.2023.100785","article-title":"Atrial fibrillation: Pathophysiology, genetic and epigenetic mechanisms","volume":"37","author":"Vinciguerra","year":"2024","journal-title":"Lancet Reg. 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