{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:24:50Z","timestamp":1789683890033,"version":"4.0.1"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>FLNC<\/jats:italic>\n                      gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy, which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in\n                      <jats:italic>FLNC<\/jats:italic>\n                      (\n                      <jats:italic>FLNC<\/jats:italic>\n                      <jats:sub>LOF<\/jats:sub>\n                      ) would have increased odds for arrhythmogenic cardiomyopathy-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We identified rare, putative\n                      <jats:italic>FLNC<\/jats:italic>\n                      <jats:sub>LOF<\/jats:sub>\n                      among 171\u2009948 individuals with exome sequencing linked to health records. Associations with arrhythmogenic cardiomyopathy phenotypes from available diagnoses and cardiac evaluations were investigated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Sixty individuals (0.03%; median age 58 years [47\u201370 interquartile range], 43% male) harbored 27 unique\n                      <jats:italic>FLNC<\/jats:italic>\n                      <jats:sub>LOF<\/jats:sub>\n                      . These individuals had significantly increased odds ratios for dilated cardiomyopathy (odds ratio, 4.9 [95% CI, 2.6\u20137.6];\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.001), supraventricular tachycardia (odds ratio, 3.2 [95% CI, 1.1\u20135.6];\n                      <jats:italic>P<\/jats:italic>\n                      =0.048), and left-dominant arrhythmogenic cardiomyopathy (odds ratio, 4.2 [95% CI, 1.4\u20137.9];\n                      <jats:italic>P<\/jats:italic>\n                      =0.03). Echocardiography revealed reduced left ventricular ejection fraction (52\u00b113% versus 57\u00b19%;\n                      <jats:italic>P<\/jats:italic>\n                      =0.001) associated with\n                      <jats:italic>FLNC<\/jats:italic>\n                      <jats:sub>LOF<\/jats:sub>\n                      . Overall, at least 9% of\n                      <jats:italic>FLNC<\/jats:italic>\n                      <jats:sub>LOF<\/jats:sub>\n                      patients demonstrated evidence of penetrant disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>FLNC<\/jats:italic>\n                      <jats:sub>LOF<\/jats:sub>\n                      variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of\n                      <jats:italic>FLNC<\/jats:italic>\n                      for actionable secondary findings.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.121.003645","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T11:30:23Z","timestamp":1655206223000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Loss-of-Function\n                    <i>FLNC<\/i>\n                    Variants Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8184-8676","authenticated-orcid":true,"given":"Eric D.","family":"Carruth","sequence":"first","affiliation":[{"name":"Department of Translational Data Science and Informatics (E.D.C., H.L.K., 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PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9262-9433","authenticated-orcid":true,"given":"Hugh","family":"Calkins","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-8584","authenticated-orcid":true,"given":"Brittney","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal","family":"Tichnell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6839-7786","authenticated-orcid":true,"given":"Amy C.","family":"Sturm","sequence":"additional","affiliation":[{"name":"The Heart Institute (M.Q., A.A., A.C.S., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Genomic Medicine Institute (M.A.K., A.C.S.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Regeneron Genetics Center","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-3396","authenticated-orcid":true,"given":"Aris","family":"Baras","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Tarrytown, NY (A.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2557-6749","authenticated-orcid":true,"given":"H.","family":"Lester 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