{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:05:41Z","timestamp":1770739541770,"version":"3.49.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,8,1]],"date-time":"2021-08-01T00:00:00Z","timestamp":1627776000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Using a discovery sample of 29\u2009000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100\u2009000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We found that rare variants associated with population-based electrocardiographic intervals identify established monogenic SCD genes (\n              <jats:italic>KCNQ1<\/jats:italic>\n              ,\n              <jats:italic>KCNH2<\/jats:italic>\n              , and\n              <jats:italic>SCN5A<\/jats:italic>\n              ), a controversial monogenic SCD gene (\n              <jats:italic>KCNE1<\/jats:italic>\n              ), and novel genes (\n              <jats:italic>PAM<\/jats:italic>\n              and\n              <jats:italic>MFGE8<\/jats:italic>\n              ) involved in cardiac conduction. Loss-of-function and pathogenic\n              <jats:italic>SCN5A<\/jats:italic>\n              variants, carried by 0.1% of individuals, were associated with a nearly 6-fold increased odds of the first-degree atrioventricular block (\n              <jats:italic>P<\/jats:italic>\n              =8.4\u00d710\n              <jats:sup>\u22125<\/jats:sup>\n              ). Similar variants in\n              <jats:italic>KCNQ1<\/jats:italic>\n              and\n              <jats:italic>KCNH2<\/jats:italic>\n              (0.2% of individuals) were associated with a 23-fold increased odds of marked corrected QT interval prolongation (\n              <jats:italic>P<\/jats:italic>\n              =4\u00d710\n              <jats:sup>\u221225<\/jats:sup>\n              ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.120.003300","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T16:00:21Z","timestamp":1627488021000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis"],"prefix":"10.1161","volume":"14","author":[{"given":"Seung Hoan","family":"Choi","sequence":"first","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher M.","family":"Haggerty","sequence":"additional","affiliation":[{"name":"Department of Translational Data Science and Informatics (C.M.H., B.K.F.), Geisinger, Danville, PA."},{"name":"Heart Institute (C.M.H., B.K.F.), Geisinger, Danville, PA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1454-3650","authenticated-orcid":true,"given":"Amelia W.","family":"Hall","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)."},{"name":"Cardiovascular Research Center (A.W.H., V.N.M., L.-C.W., P.T.E., S.A.L.), Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1454-3650","authenticated-orcid":true,"given":"Jennifer L.","family":"Halford","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA (S.H.C., S.J.J., A.W.H., J.L.H., V.N.M., L.-C.W., M.D.C., C.J.-Y.L., H.L.R., C.R., P.T.E., S.A.L.)."},{"name":"Harvard Medical School (J.L.H., C.A.-T., H.L.R.), Boston, MA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie N.","family":"Morrill","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics and Cardiovascular Disease 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