{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T07:22:20Z","timestamp":1793690540175,"version":"4.5.1"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:00:00Z","timestamp":1619740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Mutations in the <jats:italic>TTN<\/jats:italic> gene are the most common causes of dilated cardiomyopathy (DCM). The clinical significance of <jats:italic>TTN<\/jats:italic> gene variants remains inadequately understood.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Whole-exome sequencing and phenotypic characterisation were performed, and patients were followed up for a median of 44 months.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We analyzed the association of the <jats:italic>TTN<\/jats:italic> variants with the clinical outcomes in a prospective study of 1,041 patients with sporadic DCM. <jats:italic>TTN<\/jats:italic> truncating variants (tTTN) were detected in 120 (11.5%) patients as compared with 2.4\/10,000 East Asian populations in the Genome Aggregation Database (GnomAD; <jats:italic>p<\/jats:italic> &amp;lt; 0.0001). Pathogenic <jats:italic>TTN<\/jats:italic> missense variants were also enriched in DCM as compared with the GnomAD populations (27.6 vs. 5.9%, <jats:italic>p<\/jats:italic> &amp;lt; 0.0001). DCM patients with tTTN had a lower left ventricular ejection fraction (28.89 \u00b1 8.72 vs. 31.81 \u00b1 9.97, <jats:italic>p<\/jats:italic> = 0.002) and a lower frequency of the left bundle branch block (3.3 vs. 11.3%, <jats:italic>p<\/jats:italic> = 0.011) than those without or with mutations in other known causal genes (OCG). However, tTTN were not associated with the composite primary endpoint of cardiac death and heart transplantation during the follow-up period [adjusted hazard ratio (HR): 0.912; 95% confidence interval: 0.464\u20131.793; <jats:italic>p<\/jats:italic> = 0.790]. There was also no sex-dependent effect. Concomitant tTTN and pathogenic variants in OCG were present in only eight DCM patients and did not affect the outcome.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> The phenotype of DCM caused by tTTN, major causes of sporadic DCM, is not distinctly different from those caused by other causal genes for DCM.<\/jats:p>","DOI":"10.3389\/fcvm.2021.657689","type":"journal-article","created":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T07:19:47Z","timestamp":1619767187000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy"],"prefix":"10.3389","volume":"8","author":[{"given":"Lei","family":"Xiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenze","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanghui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoran","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leming","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali J.","family":"Marian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao Wen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1810","DOI":"10.1161\/CIR.0b013e31829e8807","article-title":"2013 ACCF\/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation\/American Heart Association Task Force on practice guidelines","volume":"128","author":"Yancy","year":"2013","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1093\/eurheartj\/ehv727","article-title":"Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases","volume":"37","author":"Pinto","year":"2016","journal-title":"Eur Heart J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated cardiomyopathy: genetic determinants and mechanisms","volume":"121","author":"McNally","year":"2017","journal-title":"Circ Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/j.ejheart.2007.04.003","article-title":"Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology","volume":"9","author":"Metra","year":"2007","journal-title":"Eur J Heart Fail"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.3978\/j.issn.2072-1439.2014.06.44","article-title":"Adult heart transplant: indications and outcomes","volume":"6","author":"Alraies","year":"2014","journal-title":"J Thorac Dis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1161\/01.CIR.80.3.564","article-title":"Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. 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