{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:25:29Z","timestamp":1777415129802,"version":"3.51.4"},"reference-count":25,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,6,28]],"date-time":"2020-06-28T00:00:00Z","timestamp":1593302400000},"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\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007225","name":"MOST","doi-asserted-by":"publisher","award":["106-2314-B-002-217-MY3"],"award-info":[{"award-number":["106-2314-B-002-217-MY3"]}],"id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007225","name":"MOST","doi-asserted-by":"publisher","award":["107-2314-B-002-266-MY3"],"award-info":[{"award-number":["107-2314-B-002-266-MY3"]}],"id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Recently, the spectrum of background mutation in the genes implicated in sudden arrhythmic death syndrome (SADS), has been elucidated in the Caucasian populations. However, this information is largely unknown in the Asian populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>We assessed the background rare variants (minor allele frequency &amp;lt; 0.01) of major SADS genes in whole genome sequence data of 1514 healthy Taiwanese subjects from the Taiwan Biobank. We found up to 45% of healthy subjects have a rare variant in at least one of the major SADS genes. Around 3.44% of healthy subjects had multiple mutations in one or multiple genes. The background mutation rates in long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular cardiomyopathy genes were similar, but those in Brugada syndrome (BrS) (SCN5A) and hypertrophic cardiomyopathy (HCM) genes (MYBPC3, MYH7, and TNNT2) were higher, compared to those reported in the Caucasian populations. Furthermore, the rate of incidental pathogenic variant was highest in MYBPC3 gene. Finally, the number of variant was proportional to the exon length of the gene (R2 = 0.486, P = 0.0056) but not related to its functional or evolutionary importance (degree of evolutionary conservation) (R2 = 0.0008, P = 0.9218), suggesting that the mutation was random. The ratio of variant number over exon nucleotide length was highest in MYBPC3, MYH7, and TNNT2 genes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Unique features of background SADS gene mutation in the Asian populations include higher prevalence of incidental variant in HCM, BrS, and long QT 3 (SCN5A) genes. HCM genes have the highest variant number per exon length.<\/jats:p><\/jats:sec>","DOI":"10.1093\/europace\/euaa092","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T11:28:44Z","timestamp":1589974124000},"page":"1287-1297","source":"Crossref","is-referenced-by-count":7,"title":["Prevalence of sudden arrhythmic death syndrome-related genetic mutations in an Asian cohort of whole genome sequence"],"prefix":"10.1093","volume":"22","author":[{"given":"Pang-Shuo","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Shan","family":"Hsieh","sequence":"additional","affiliation":[{"name":"College of Life Science, Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng-Nan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jien-Jiun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fu-Chun","family":"Chiu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cho-Kai","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine and Cardiovascular center, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juey-Jen","family":"Hwang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine and Cardiovascular center, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric Y","family":"Chuang","sequence":"additional","affiliation":[{"name":"College of Life Science, Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan"},{"name":"Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Ti","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine and Cardiovascular center, National Taiwan University College of Medicine and Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,28]]},"reference":[{"key":"2020080404503672200_euaa092-B1","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCULATIONAHA.111.023838","article-title":"Epidemiology and genetics of sudden cardiac death","volume":"125","author":"Deo","year":"2012","journal-title":"Circulation"},{"key":"2020080404503672200_euaa092-B2","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1161\/CIRCRESAHA.117.309711","article-title":"Classification, epidemiology, and global burden of cardiomyopathies","volume":"121","author":"McKenna","year":"2017","journal-title":"Circ Res"},{"key":"2020080404503672200_euaa092-B3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.hlc.2018.09.007","article-title":"Channelopathies that lead to sudden cardiac death: clinical and genetic aspects","volume":"28","author":"Skinner","year":"2019","journal-title":"Heart Lung Circ"},{"key":"2020080404503672200_euaa092-B4","doi-asserted-by":"crossref","first-page":"s17","DOI":"10.7861\/clinmedicine.18-2-s17","article-title":"Sudden cardiac death in the young: a genetic destiny?","volume":"18","author":"Thiene","year":"2018","journal-title":"Clin Med (Lond"},{"key":"2020080404503672200_euaa092-B5","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12265-014-9542-z","article-title":"Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise","volume":"7","author":"Kapplinger","year":"2014","journal-title":"J Cardiovasc Transl Res"},{"key":"2020080404503672200_euaa092-B6","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/gim.2017.40","article-title":"Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing","volume":"19","author":"Haggerty","year":"2017","journal-title":"Genet Med"},{"key":"2020080404503672200_euaa092-B7","doi-asserted-by":"crossref","first-page":"E332","DOI":"10.3390\/jcm8030332","article-title":"Genome-wide copy number variation association study of atrial fibrillation related thromboembolic stroke","volume":"8","author":"Hsieh","year":"2019","journal-title":"J Clin Med"},{"key":"2020080404503672200_euaa092-B8","first-page":"5321","article-title":"Population structure of Han Chinese in the modern Taiwanese population based on 10,000 participants in the Taiwan Biobank project","volume":"25","author":"Chen","year":"2016","journal-title":"Hum Mol Genet"},{"key":"2020080404503672200_euaa092-B9","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.jfma.2013.02.002","article-title":"Unique clinical characteristics and SCN5A mutations in patients with Brugada syndrome in Taiwan","volume":"114","author":"Juang","year":"2015","journal-title":"J Formos Med Assoc"},{"key":"2020080404503672200_euaa092-B10","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jjcc.2014.05.010","article-title":"Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan","volume":"65","author":"Chiou","year":"2015","journal-title":"J Cardiol"},{"key":"2020080404503672200_euaa092-B11","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.3760\/cma.j.issn.0366-6999.20131813","article-title":"Clinical characteristics of patients with congenital long QT syndrome and bigenic mutations","volume":"127","author":"Jimmy","year":"2014","journal-title":"Chin Med J (Engl)"},{"key":"2020080404503672200_euaa092-B12","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"2020080404503672200_euaa092-B13","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ajhg.2017.01.004","article-title":"InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines","volume":"100","author":"Li","year":"2017","journal-title":"Am J Hum Genet"},{"key":"2020080404503672200_euaa092-B14","doi-asserted-by":"crossref","first-page":"e004742","DOI":"10.1161\/CIRCEP.116.004742","article-title":"Interpreting incidentally identified variants in genes associated with catecholaminergic polymorphic ventricular tachycardia in a large cohort of clinical whole-exome genetic test referrals","volume":"10","author":"Landstrom","year":"2017","journal-title":"Circ Arrhythm Electrophysiol"},{"key":"2020080404503672200_euaa092-B15","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/nrg2808","article-title":"Mutational effects and the evolution of new protein functions","volume":"11","author":"Soskine","year":"2010","journal-title":"Nat Rev Genet"},{"key":"2020080404503672200_euaa092-B16","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1161\/CIRCULATIONAHA.109.863076","article-title":"Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants","volume":"120","author":"Kapa","year":"2009","journal-title":"Circulation"},{"key":"2020080404503672200_euaa092-B17","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1161\/CIRCGENETICS.112.963421","article-title":"Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation","volume":"5","author":"Pan","year":"2012","journal-title":"Circ Cardiovasc Genet"},{"key":"2020080404503672200_euaa092-B18","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1016\/j.jacc.2010.12.036","article-title":"Distinguishing arrhythmogenic right ventricular cardiomyopathy\/dysplasia-associated mutations from background genetic noise","volume":"57","author":"Kapplinger","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"2020080404503672200_euaa092-B19","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1161\/CIRCGENETICS.113.000367","article-title":"Arrhythmogenic right ventricular cardiomyopathy: growing evidence for complex inheritance","volume":"6","author":"Lodder","year":"2013","journal-title":"Circ Cardiovasc Genet"},{"key":"2020080404503672200_euaa092-B20","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1161\/CIRCRESAHA.116.304030","article-title":"Genetics of sudden cardiac death","volume":"116","author":"Bezzina","year":"2015","journal-title":"Circ Res"},{"key":"2020080404503672200_euaa092-B21","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/S0735-1097(16)30681-7","article-title":"Genetic variants in patients with brugada syndrome","volume":"67","author":"O\u2019Donnell","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2020080404503672200_euaa092-B22","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.hrthm.2018.02.031","article-title":"Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise","volume":"15","author":"Landstrom","year":"2018","journal-title":"Heart Rhythm"},{"key":"2020080404503672200_euaa092-B23","doi-asserted-by":"crossref","first-page":"e005009","DOI":"10.1161\/JAHA.116.005009","article-title":"SCN5A genetic polymorphisms associated with increased defibrillator shocks in brugada syndrome","volume":"6","author":"Makarawate","year":"2017","journal-title":"J Am Heart Assoc"},{"key":"2020080404503672200_euaa092-B24","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1161\/CIRCGENETICS.109.853374","article-title":"SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome","volume":"2","author":"Probst","year":"2009","journal-title":"Circ Cardiovasc Genet"},{"key":"2020080404503672200_euaa092-B25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.joa.2013.01.008","article-title":"Genetic basis of Brugada syndrome","volume":"29","author":"Horie","year":"2013","journal-title":"J Arrhythm"}],"container-title":["EP Europace"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/europace\/article-pdf\/22\/8\/1287\/33560985\/euaa092.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/europace\/article-pdf\/22\/8\/1287\/33560985\/euaa092.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T02:13:51Z","timestamp":1722910431000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/europace\/article\/22\/8\/1287\/5864440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,28]]},"references-count":25,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,6,28]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/europace\/euaa092","relation":{},"ISSN":["1099-5129","1532-2092"],"issn-type":[{"value":"1099-5129","type":"print"},{"value":"1532-2092","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8]]},"published":{"date-parts":[[2020,6,28]]}}}