{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T17:13:51Z","timestamp":1791911631296,"version":"4.3.4"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,7,2]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiopathic dilated cardiomyopathy (DCM). However, a comprehensive genomics-first evaluation of the impact of TTNtvs in different clinical contexts, and the evaluation of modifiers such as genetic ancestry, has not been performed.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We reviewed whole exome sequence data for &gt;71\u2009000 individuals (61\u2009040 from the Geisinger MyCode Community Health Initiative (2007 to present) and 10\u2009273 from the PennMedicine BioBank (2013 to present) to identify anyone with TTNtvs. We further selected individuals with TTNtvs in exons highly expressed in the heart (proportion spliced in [PSI] &gt;0.9). Using linked electronic health records, we evaluated associations of TTNtvs with diagnoses and quantitative echocardiographic measures, including subanalyses for individuals with and without DCM diagnoses. We also reviewed data from the Jackson Heart Study to validate specific analyses for individuals of African ancestry.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Identified with a TTNtv in a highly expressed exon (hiPSI) were 1.2% individuals in PennMedicine BioBank and 0.6% at Geisinger. The presence of a hiPSI TTNtv was associated with increased odds of DCM in individuals of European ancestry (odds ratio [95% CI]: 18.7 [9.1\u201339.4] {PennMedicine BioBank} and 10.8 [7.0\u201316.0] {Geisinger}). hiPSI TTNtvs were not associated with DCM in individuals of African ancestry, despite a high DCM prevalence (odds ratio, 1.8 [0.2\u201313.7];\n              <jats:italic>P<\/jats:italic>\n              =0.57). Among 244 individuals of European ancestry with DCM in PennMedicine BioBank, hiPSI TTNtv carriers had lower left ventricular ejection fraction (\u03b2=\u201312%,\n              <jats:italic>P<\/jats:italic>\n              =3\u00d710\n              <jats:sup>\u20137<\/jats:sup>\n              ), and increased left ventricular diameter (\u03b2=0.65 cm,\n              <jats:italic>P<\/jats:italic>\n              =9\u00d710\n              <jats:sup>\u20133<\/jats:sup>\n              ). In the Geisinger cohort, hiPSI TTNtv carriers without a cardiomyopathy diagnosis had more atrial fibrillation (odds ratio, 2.4 [1.6\u20133.6]) and heart failure (odds ratio, 3.8 [2.4\u20136.0]), and lower left ventricular ejection fraction (\u03b2=\u20133.4%,\n              <jats:italic>P<\/jats:italic>\n              =1\u00d710\n              <jats:sup>\u20137<\/jats:sup>\n              ).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Individuals of European ancestry with hiPSI TTNtv have an abnormal cardiac phenotype characterized by lower left ventricular ejection fraction, irrespective of the clinical manifestation of cardiomyopathy. Associations with arrhythmias, including atrial fibrillation, were observed even when controlling for cardiomyopathy diagnosis. In contrast, no association between hiPSI TTNtvs and DCM was discerned among individuals of African ancestry. Given these findings, clinical identification of hiPSI TTNtv carriers may alter clinical management strategies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.039573","type":"journal-article","created":{"date-parts":[[2019,6,20]],"date-time":"2019-06-20T09:00:36Z","timestamp":1561021236000},"page":"42-54","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":147,"title":["Genomics-First Evaluation of Heart Disease Associated With Titin-Truncating Variants"],"prefix":"10.1161","volume":"140","author":[{"given":"Christopher M.","family":"Haggerty","sequence":"first","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Damrauer","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. Babu, M.M., A.S., H.W., K.B.M., T.P.C., A.V., X.Z., M.D.R., D.J.R., Z.A.)."},{"name":"Corporal Michael Crescenz VA Medical Center, Philadelphia, PA (S.M.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Levin","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. Babu, M.M., A.S., H.W., K.B.M., T.P.C., A.V., X.Z., M.D.R., D.J.R., Z.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Birtwell","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. Babu, M.M., A.S., H.W., K.B.M., T.P.C., A.V., X.Z., M.D.R., D.J.R., Z.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Carey","sequence":"additional","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia M.","family":"Golden","sequence":"additional","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin N.","family":"Hartzel","sequence":"additional","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yirui","family":"Hu","sequence":"additional","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renae","family":"Judy","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. 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Babu, M.M., A.S., H.W., K.B.M., T.P.C., A.V., X.Z., M.D.R., D.J.R., Z.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Lester Kirchner","sequence":"additional","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph B.","family":"Leader","sequence":"additional","affiliation":[{"name":"Geisinger, Danville, PA (C.M.H., D.J.C., A.M.G., D.N.H., Y.H., M.A.K., H.L.K., J.B.L., Z.N., T.N.P., A.P., D.T.S., R.C.S., A.C.S., M.F.M., B.K.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lusha","family":"Liang","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. Babu, M.M., A.S., H.W., K.B.M., T.P.C., A.V., X.Z., M.D.R., D.J.R., Z.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"McDermott-Roe","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. Babu, M.M., A.S., H.W., K.B.M., T.P.C., A.V., X.Z., M.D.R., D.J.R., Z.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apoorva","family":"Babu","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.M.D., M.G.L., D.B., R.J., R.L.K., L.L., C.M.-R., A. 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