{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:34:02Z","timestamp":1791408842369,"version":"4.3.3"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"\n Background<\/jats:title>\n \n Mutations in the\n CACNA1C<\/jats:italic>\n gene\u2013encoding for the major Ca\n 2+<\/jats:sup>\n channel of the heart\u2013may exhibit a variety of clinical manifestations. These include typical or atypical Timothy syndromes (TS) which are associated with multiple organ manifestations, and cardiac involvement in form of malignant arrhythmias, QTc prolongation, or AV block. \u201cCardiac only\u201d Timothy syndrome (COTS) shows no extracardiac manifestation, whereas some\n CACNA1C<\/jats:italic>\n gene mutations are associated with QTc prolongation alone (isolated long QT syndrome 8, LQT8).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n A systematic search of the literature reporting cases of\n CACNA1C<\/jats:italic>\n gene mutation associated syndromes, including TS, COTS and isolated LQT8\n via<\/jats:italic>\n major databases published from 2004 through 2019 was performed. Detailed patient-level phenotypic and genotypic characteristics, as well as long-term outcome measures were collected and compared between pre-specified patient groups, defined both on phenotype and genotype.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 59 TS, 6 COTS, and 20 isolated LQT8 index cases were identified. Apart of syndactyly or baldness, there were no major differences regarding clinical manifestations or outcome measures between TS subtypes, either defining TS subtypes on the genotype or based on the phenotype. Both subtypes were characterized by an extreme degree of QTc prolongation (median \u2265600 ms) which were reflected in high major adverse cardiac event rate. On the other hand, there were marked differences between TS, COTS, and isolated LQT8. Timothy syndrome was characterized by a much earlier disease onset, much more pronounced QTc prolongation and much higher mortality rate than COTS or isolated LQT8. Similar differences were observed comparing\n CACNA1C<\/jats:italic>\n exon 8\/8A vs. non-exon 8\/8A mutation carriers. TS showed a high degree of genetic homogeneity, as the p.Gly406Arg mutation either in exon 8 or exon 8A alone was responsible for 70% of the cases.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Clinical phenotypes associated with mutations in the\n CACNA1C<\/jats:italic>\n gene show important clinical differences. Timothy syndrome is associated with the most severe clinical phenotype and with the highest risk of morbidity and mortality. However, distinguishing TS subtypes, in any form, are not supported by our data.\n <\/jats:p>\n <\/jats:sec>\n \n Systematic review registration<\/jats:title>\n \n [\n https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:ext-link>\n ], identifier [CRD42020184737].\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fcvm.2022.1021009","type":"journal-article","created":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T03:50:32Z","timestamp":1669693832000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Geno- and phenotypic characteristics and clinical outcomes of CACNA1C gene mutation associated Timothy syndrome, \u201ccardiac only\u201d Timothy syndrome and isolated long QT syndrome 8: A systematic review"],"prefix":"10.3389","volume":"9","author":[{"given":"J\u00e1nos","family":"Borb\u00e1s","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1t\u00e9","family":"V\u00e1mos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Hategan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilla","family":"Han\u00e1k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelli","family":"Farkas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Szak\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezs\u0151","family":"Csupor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e1lint","family":"T\u00e9l","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Kup\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Be\u00e1ta","family":"Cs\u00e1nyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikt\u00f3ria","family":"Nagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Kom\u00f3csi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tam\u00e1s","family":"Habon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Hegyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00f3bert","family":"Sepp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1124\/pr.57.4.4","article-title":"International union of pharmacology. 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