{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:41:03Z","timestamp":1791348063661,"version":"4.3.1"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2005,8,30]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant\n            <jats:italic>KCNH2<\/jats:italic>\n            mutation along with a common single nucleotide polymorphism in the same gene.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense\n            <jats:italic>KCNH2<\/jats:italic>\n            mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common\n            <jats:italic>KCNH2<\/jats:italic>\n            polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of\n            <jats:italic>KCNH2<\/jats:italic>\n            -K897T is predicted to exaggerate the\n            <jats:italic>I<\/jats:italic>\n            <jats:sub>\n              <jats:italic>Kr<\/jats:italic>\n            <\/jats:sub>\n            reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            We have provided evidence that a common\n            <jats:italic>KCNH2<\/jats:italic>\n            polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.105.549071","type":"journal-article","created":{"date-parts":[[2005,8,23]],"date-time":"2005-08-23T00:34:03Z","timestamp":1124757243000},"page":"1251-1258","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":214,"title":["<i>KCNH2<\/i>\n            -K897T Is a Genetic Modifier of Latent Congenital Long-QT Syndrome"],"prefix":"10.1161","volume":"112","author":[{"given":"Lia","family":"Crotti","sequence":"first","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Lundquist","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Insolia","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Pedrazzini","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Ferrandi","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano M.","family":"De Ferrari","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Vicentini","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan M.","family":"Roden","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Alfred L.","family":"George","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology (L.C., G.M.D.F., A.V., P.J.S.), University of Pavia, and IRCCS Policlinico S. Matteo, Pavia; Molecular Cardiology Laboratory (L.C., R.I., M.P., C.F., P.J.S.), IRCCS Policlinico S. Matteo, Pavia, Italy; and the Departments of Pharmacology (A.L.L., P.Y., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(75)90089-7"},{"key":"e_1_3_3_2_2","unstructured":"Schwartz PJ Priori SG Napolitano C. The long QT syndrome. In: Zipes DP Jalife J eds. 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