{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T10:08:05Z","timestamp":1782727685197,"version":"3.54.5"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with variants in desmosome genes. Secondary findings of pathogenic\/likely pathogenic variants, primarily loss-of-function (LOF) variants, are recommended for clinical reporting; however, their prevalence and associated phenotype in a general clinical population are not fully characterized.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              From whole-exome sequencing of 61\u2009019 individuals in the DiscovEHR cohort, we screened for putative loss-of-function variants in\n              <jats:italic>PKP2<\/jats:italic>\n              ,\n              <jats:italic>DSC2<\/jats:italic>\n              ,\n              <jats:italic>DSG2<\/jats:italic>\n              , and\n              <jats:italic>DSP<\/jats:italic>\n              . We evaluated measures from prior clinical ECG and echocardiograms, manually over-read to evaluate ARVC diagnostic criteria, and performed a PheWAS (phenome-wide association study). Finally, we estimated expected penetrance using Bayesian inference.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              One hundred forty individuals (0.23%; 59\u00b118 years old at last encounter; 33% male) had an ARVC variant (G\n              <jats:sup>+<\/jats:sup>\n              ). None had an existing diagnosis of ARVC in the electronic health record, nor significant differences in prior ECG or echocardiogram findings compared with matched controls without variants. Several G\n              <jats:sup>+<\/jats:sup>\n              individuals satisfied major repolarization (n=4) and ventricular function (n=5) criteria, but this prevalence matched controls. PheWAS showed no significant associations of other heart disease diagnoses. Combining our best genetic and disease prevalence estimates yields an estimated penetrance of 6.0%.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>The prevalence of ARVC loss-of-function variants is \u22481:435 in a general clinical population of predominantly European descent, but with limited electronic health record-based evidence of phenotypic association in our population, consistent with a low penetrance estimate. Prospective deep phenotyping and longitudinal follow-up of a large sequenced cohort is needed to determine the true clinical relevance of an incidentally identified ARVC loss-of-function variant.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002579","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T19:00:36Z","timestamp":1574190036000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function Genetic Variants in Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes"],"prefix":"10.1161","volume":"12","author":[{"given":"Eric D.","family":"Carruth","sequence":"first","affiliation":[{"name":"Department of Imaging Science and Innovation (E.D.C., L.J., S.R., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson","family":"Young","sequence":"additional","affiliation":[{"name":"The Heart Institute (W.Y., D.B., A.A., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Beer","sequence":"additional","affiliation":[{"name":"The Heart Institute (W.Y., D.B., A.A., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"James","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (C.A.J., H.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugh","family":"Calkins","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (C.A.J., H.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linyuan","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Imaging Science and Innovation (E.D.C., L.J., S.R., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushravya","family":"Raghunath","sequence":"additional","affiliation":[{"name":"Department of Imaging Science and Innovation (E.D.C., L.J., S.R., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin N.","family":"Hartzel","sequence":"additional","affiliation":[{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph B.","family":"Leader","sequence":"additional","affiliation":[{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Lester","family":"Kirchner","sequence":"additional","affiliation":[{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane T.","family":"Smelser","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics (D.T.S., D.J.C.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Carey","sequence":"additional","affiliation":[{"name":"Department of Molecular and Functional Genomics (D.T.S., D.J.C.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute (M.A.K., A.C.S.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C.","family":"Sturm","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute (M.A.K., A.C.S.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amro","family":"Alsaid","sequence":"additional","affiliation":[{"name":"The Heart Institute (W.Y., D.B., A.A., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon K.","family":"Fornwalt","sequence":"additional","affiliation":[{"name":"Department of Imaging Science and Innovation (E.D.C., L.J., S.R., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"The Heart Institute (W.Y., D.B., A.A., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Department of Radiology (B.K.F.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher M.","family":"Haggerty","sequence":"additional","affiliation":[{"name":"Department of Imaging Science and Innovation (E.D.C., L.J., S.R., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"Biomedical and Translational Informatics Institute (E.D.C., L.J., S.R., D.N.H., J.B.L., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA."},{"name":"The Heart Institute (W.Y., D.B., A.A., B.K.F., C.M.H.), Geisinger, Danville, PA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60256-7"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198801213180301"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199808063390602"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2016.01.026"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2011.173"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.114.001003"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.05.020"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.190"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.04.009"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.187"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.118.002237"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2012.283"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.12.036"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.863076"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.17701"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.40"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2003.10.037"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.90"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.06.022"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.039573"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0625-8"},{"key":"e_1_3_4_25_2","first-page":"S1547-5271(19)3","article-title":"2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy.","author":"Towbin JA","year":"2019","unstructured":"Towbin, JA, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. 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