{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T07:50:00Z","timestamp":1782460200318,"version":"3.54.5"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy, found in \u226425% of familial cases. Moreover, TTNtv associated with dilated cardiomyopathy are estimated to be present in 0.5% of the general population. The prognosis of asymptomatic carriers of TTNtv is poorly understood because TTNtv are associated with a highly variable phenotype. We aim to assess the natural history and clinical relevance of TTNtv by analyzing standardized mortality ratios (SMR) in multigenerational pedigrees and in close relatives of present-day patients.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Haplotype and genealogical analyses were performed on 3 recurrent TTNtv. Subsequently, the family tree mortality ratio method was used to compare all-cause mortality of subjects at an a priori 50% risk of carrying TTNtv to the general Dutch population. SMRs were stratified for sex, age, and calendar period. Subgroups were compared with Poisson regression. Similarly, SMRs were calculated in parents of 128 present-day dilated cardiomyopathy probands with TTNtv using the reverse parent-offspring method.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              The TTNtv were established as founder mutations and traced to 18th century ancestors. In 20\u2009522 person-years, overall mortality was not significantly increased (SMR, 1.06; 95% CI, 0.95\u20131.18;\n              <jats:italic>P<\/jats:italic>\n              =0.162). However, mortality was significantly increased in subjects living after 1965 (SMR, 1.27; 95% CI, 1.04\u20131.53;\n              <jats:italic>P<\/jats:italic>\n              =0.009) and aged \u226560 years (SMR, 1.17; 95% CI, 1.01\u20131.35;\n              <jats:italic>P<\/jats:italic>\n              =0.02). The reverse parent-offspring analysis showed overall excess mortality (SMR, 1.26; 95% CI, 1.07\u20131.48;\n              <jats:italic>P<\/jats:italic>\n              =0.003), driven by subjects aged \u226560 years.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The natural history of the analyzed TTNtv shows a relatively mild disease course with significant excess mortality in elderly patients. With increasing life expectancy, TTNtv-associated morbidity and mortality will likely become more prevalent.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.118.002436","type":"journal-article","created":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T18:08:43Z","timestamp":1558462123000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Mortality Risk Associated With Truncating Founder Mutations in Titin"],"prefix":"10.1161","volume":"12","author":[{"given":"Mark","family":"Jansen","sequence":"first","affiliation":[{"name":"Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette F.","family":"Baas","sequence":"additional","affiliation":[{"name":"Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin Y.","family":"van Spaendonck-Zwarts","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (K.Y.v.S.-Z., R.H.L.D., A.C.H.), Amsterdam University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber S.","family":"Ummels","sequence":"additional","affiliation":[{"name":"Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"van den Wijngaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Center, the Netherlands (A.v.d.W., P.J.T.M.H.-v.d.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan D.H.","family":"Jongbloed","sequence":"additional","affiliation":[{"name":"Department of Genetics (J.D.H.J., E.T.H., J.P.v.T.), University Medical Centre Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon A.","family":"van Slegtenhorst","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (M.A.v.S., M.W.W.), Erasmus Medical Centre, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald H.","family":"Lekanne Deprez","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (K.Y.v.S.-Z., R.H.L.D., A.C.H.), Amsterdam University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja W.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (M.A.v.S., M.W.W.), Erasmus Medical Centre, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Michels","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.M.), Erasmus Medical Centre, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan C.","family":"Houweling","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics (K.Y.v.S.-Z., R.H.L.D., A.C.H.), Amsterdam University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar T.","family":"Hoorntje","sequence":"additional","affiliation":[{"name":"Department of Genetics (J.D.H.J., E.T.H., J.P.v.T.), University Medical Centre Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula J.T.M.","family":"Helderman-van den Enden","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Center, the Netherlands (A.v.d.W., P.J.T.M.H.-v.d.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela Q.C.M.","family":"Barge-Schaapveld","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Centre, the Netherlands (D.Q.C.M.B.-S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Peter van Tintelen","sequence":"additional","affiliation":[{"name":"Department of Genetics (J.D.H.J., E.T.H., J.P.v.T.), University Medical Centre Groningen, University of Groningen, the Netherlands."},{"name":"Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands (J.P.v.T., F.W.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten P.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.P.v.d.B.), University Medical Centre Groningen, University of Groningen, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.M.","family":"Wilde","sequence":"additional","affiliation":[{"name":"Department of Cardiology (A.A.M.W.), Amsterdam University Medical Center, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans K.","family":"Ploos van Amstel","sequence":"additional","affiliation":[{"name":"Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.M.","family":"Hennekam","sequence":"additional","affiliation":[{"name":"Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert W.","family":"Asselbergs","sequence":"additional","affiliation":[{"name":"Division of Heart and Lungs, Department of Cardiology (F.W.A.), University Medical Center Utrecht, Utrecht University, the Netherlands."},{"name":"Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands (J.P.v.T., F.W.A.)."},{"name":"Institute of Cardiovascular Science (F.W.A.) and Health Data Research UK, Institute of Health Informatics (F.W.A.), University College London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.G.","family":"Sijbrands","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine (E.J.G.S.), Erasmus Medical Centre, Rotterdam, the Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Dooijes","sequence":"additional","affiliation":[{"name":"Department of Genetics (M.J., A.F.B., A.S.U., H.K.P.v.A., E.A.M.H., D.D.), University Medical Center Utrecht, Utrecht University, the 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