{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:08:45Z","timestamp":1784740125808,"version":"3.55.0"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>CaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>CaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Genetic studies identified 2 novel CaM variants (\n              <jats:italic>CALM3<\/jats:italic>\n              -E141K in 2 cases;\n              <jats:italic>CALM1<\/jats:italic>\n              -E141V) and one previously reported CaM pathogenic variant (\n              <jats:italic>CALM3<\/jats:italic>\n              -D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505\u2013725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multiple occurrences of intrauterine fetal demise. The mother from the family with recurrent intrauterine fetal demise exhibited the\n              <jats:italic>CALM3<\/jats:italic>\n              -E141K mutant allele in 25% of next-generation sequencing reads indicating somatic mosaicism, whereas\n              <jats:italic>CALM3<\/jats:italic>\n              -D130G was present in 6% of captured molecules of the paternal DNA sample, also indicating mosaicism. Two novel mutations (E141K and E141V) impaired Ca\n              <jats:sup>2+<\/jats:sup>\n              binding affinity to the C-domain of CaM. Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca\n              <jats:sup>2+<\/jats:sup>\n              -dependent inactivation of L-type Ca\n              <jats:sup>2+<\/jats:sup>\n              channels and prolonged action potential duration.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              We report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca\n              <jats:sup>2+<\/jats:sup>\n              channels by 2 novel CaM mutations affecting the same residue. Parental mosaicism should be suspected in families with unexplained fetal arrhythmia or fetal demise combined with a documented CaM mutation.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002581","type":"journal-article","created":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T18:00:30Z","timestamp":1568743230000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":46,"title":["Genetic Mosaicism in Calmodulinopathy"],"prefix":"10.1161","volume":"12","author":[{"given":"Lisa M.","family":"Wren","sequence":"first","affiliation":[{"name":"From the Department of Pharmacology (L.M.W., F.P., P.W.B., A.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Jim\u00e9nez-J\u00e1imez","sequence":"additional","affiliation":[{"name":"Cardiology Department (J.J.-J.), Virgen de las Nieves Hospital, Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh","family":"Al-Ghamdi","sequence":"additional","affiliation":[{"name":"Cardiac Sciences Department, Section of Pediatric Cardiology, King Abdulaziz Cardiac Center, Ministry of National Guard Health Affairs, Riyadh (S.A.-G.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jumana Y.","family":"Al-Aama","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine, Faculty of Medicine (J.Y.A.-A.), King Abdulaziz University, Jeddah"},{"name":"Princess Al Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders (J.Y.A.-A., A.B.), King Abdulaziz University, Jeddah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amnah","family":"Bdeir","sequence":"additional","affiliation":[{"name":"Princess Al Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders (J.Y.A.-A., A.B.), King Abdulaziz University, Jeddah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuhair N.","family":"Al-Hassnan","sequence":"additional","affiliation":[{"name":"The Cardiovascular Genetics Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (Z.N.A.-H.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyn L.","family":"Kuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, National University Heart Center and Cardiovascular Research Institute, National University of Singapore (J.L.K., R.Y.F.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger Y.","family":"Foo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, National University Heart Center and Cardiovascular Research Institute, National University of Singapore (J.L.K., R.Y.F.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Potet","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (L.M.W., F.P., P.W.B., A.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher N.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN (C.N.J., W.J.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam C.","family":"Aziz","sequence":"additional","affiliation":[{"name":"Department of Neurology (M.C.A., G.L.C.), Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma L.","family":"Carvill","sequence":"additional","affiliation":[{"name":"Department of Neurology (M.C.A., G.L.C.), Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan-Pablo","family":"Kaski","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science, University College London, United Kingdom (J.-P.K.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Crotti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Milano-Bicocca (L.C.)"},{"name":"IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.)"},{"name":"Cardiology Department, Health in Code SL, A Coru\u00f1a, Spain (L.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Perin","sequence":"additional","affiliation":[{"name":"Pediatric Cardiology Division (F.P.), Virgen de las Nieves Hospital, Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Monserrat","sequence":"additional","affiliation":[{"name":"Cardiology Department, Health in Code SL, A Coru\u00f1a, Spain (L.M.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W.","family":"Burridge","sequence":"additional","affiliation":[{"name":"From the Department of Pharmacology (L.M.W., F.P., P.W.B., A.L.G.), Northwestern University Feinberg School of Medicine, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., P.J.S.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Chazin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Center for Structural Biology, 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