{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:33:57Z","timestamp":1791408837740,"version":"4.3.3"},"reference-count":24,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Pathogenic variants in the L\u2010type Ca<jats:sup>2+<\/jats:sup> channel gene <jats:italic>CACNA1C<\/jats:italic> cause a multi\u2010system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in <jats:italic>CACNA1C<\/jats:italic> (p.R518C) was reported to cause cardiac\u2010only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra\u2010cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A four\u2010generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great\u2010uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In addition to displaying cardinal features of <jats:italic>CACNA1C<\/jats:italic> disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our report expands the cardiac phenotype of <jats:italic>CACNA1C<\/jats:italic> variants and reflects the variable expressivity of mutations in the L\u2010type Ca<jats:sup>2+<\/jats:sup> channel.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1673","type":"journal-article","created":{"date-parts":[[2021,4,2]],"date-time":"2021-04-02T06:25:15Z","timestamp":1617344715000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Expanding the phenotype of <i>CACNA1C<\/i> mutation disorders"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0341-0203","authenticated-orcid":false,"given":"Lindsey","family":"Gakenheimer\u2010Smith","sequence":"first","affiliation":[{"name":"Division of Pediatric Cardiology University of Utah Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Meyers","sequence":"additional","affiliation":[{"name":"Genome Medical San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Lundahl","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology University of Utah Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaji C.","family":"Menon","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology University of Utah Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Jared","family":"Bunch","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine University of Utah University of Utah Health Sciences Center Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Briana L.","family":"Sawyer","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology University of Utah Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Tristani\u2010Firouzi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology University of Utah Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan P.","family":"Etheridge","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology University of Utah Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.07.026"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000138"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.115.002745"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37297"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2013.53"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.023"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2005.50139.x"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002534"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.08.014"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.586883"},{"key":"e_1_2_6_14_1","volume-title":"Timothy syndrome","author":"Napolitano C.","year":"2006"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000013248"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502506102"},{"key":"e_1_2_6_18_1","unstructured":"Splawski I. Timothy K. Priori S. Napolitano C. &Bloise R.(1993).GeneReviews[Internet].Bookshelf ID: NBK1403 PMID 20301577."},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.011"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21599"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02588"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.7.1954"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.114.009654"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.896191"},{"issue":"5","key":"e_1_2_6_25_1","first-page":"7073","article-title":"Genetic analysis of sick sinus syndrome in a family harboring compound CACNA1C and TTN mutations","volume":"17","author":"Zhu Y. B.","year":"2018","journal-title":"Molecular Medicine Reports"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1673","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.1673","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.1673","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T02:21:48Z","timestamp":1693362108000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.1673"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4]]},"references-count":24,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,6]]}},"alternative-id":["10.1002\/mgg3.1673"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.1673","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4]]},"assertion":[{"value":"2020-10-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e1673"}}