{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:54:54Z","timestamp":1787018094353,"version":"build-2736575974"},"reference-count":21,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2015,10,29]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      The titin gene (\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      ) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness.\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      truncating mutations cause dilated cardiomyopathy (\n                      <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n                      ); however, the role of\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      missense variants in\n                      <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n                      has been difficult to elucidate because of the presence of background\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      variation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      A cohort of 147\n                      <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n                      index subjects underwent\n                      <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content>\n                      sequencing for 313\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      exons covering the N2B and N2\n                      <jats:styled-content style=\"fixed-case\">BA<\/jats:styled-content>\n                      cardiac isoforms of\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      . Of the 348 missense variants, we identified 44 \u201csevere\u201d rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another\n                      <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n                      gene) and 7 were compound heterozygotes (2\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      \u201csevere\u201d variants). Segregation analysis allowed the classification of the \u201csevere\u201d variants into 5 \u201clikely\u201d (cosegregating), 5 \u201cunlikely\u201d (noncosegregating), and 34 \u201cpossibly\u201d (where family structure precluded segregation analysis) disease\u2010causing variants. Patients with\n                      <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n                      carrying \u201clikely\u201d or \u201cpossibly\u201d pathogenic\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      \u201csevere\u201d variants did not show a different outcome compared with \u201cunlikely\u201d and noncarriers of a \u201csevere\u201d\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      variant. However, the \u201clikely\u201d and \u201cpossibly\u201d disease\u2010causing variants were overrepresented in the C\u2010zone of the A\u2010band region of the sarcomere.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although\n                      <jats:styled-content style=\"fixed-case\">DCM<\/jats:styled-content>\n                      patients carrying bioinformatically \u201csevere\u201d\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of \u201clikely\u201d and \u201cpossibly\u201d disease\u2010causing variants suggests a potential biological role for some\n                      <jats:italic>\n                        <jats:styled-content style=\"fixed-case\">TTN<\/jats:styled-content>\n                      <\/jats:italic>\n                      missense variants.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.115.002645","type":"journal-article","created":{"date-parts":[[2015,11,13]],"date-time":"2015-11-13T21:43:37Z","timestamp":1447451017000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":92,"title":["Role of Titin Missense Variants in Dilated Cardiomyopathy"],"prefix":"10.1161","volume":"4","author":[{"given":"Rene L.","family":"Begay","sequence":"first","affiliation":[{"name":"University of Colorado Denver CU\u2010Cardiovascular Institute, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Graw","sequence":"additional","affiliation":[{"name":"University of Colorado Denver CU\u2010Cardiovascular Institute, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Sinagra","sequence":"additional","affiliation":[{"name":"Cardiovascular Department \u201cOspedali Riuniti\u201d and Cardiovascular Center, 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Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Barbati","sequence":"additional","affiliation":[{"name":"Cardiovascular Department \u201cOspedali Riuniti\u201d and Cardiovascular Center, ASS1\u2010Trieste and University of Trieste, Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Spezzacatene","sequence":"additional","affiliation":[{"name":"Cardiovascular Department \u201cOspedali Riuniti\u201d and Cardiovascular Center, ASS1\u2010Trieste and University of Trieste, Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Brun","sequence":"additional","affiliation":[{"name":"Cardiovascular Department \u201cOspedali Riuniti\u201d and Cardiovascular Center, ASS1\u2010Trieste and University of Trieste, Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Di 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