{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:47:53Z","timestamp":1791330473425,"version":"4.3.1"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2007,8,14]],"date-time":"2007-08-14T00:00:00Z","timestamp":1187049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2007,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The relationship between genetic variation in the T\u2010type calcium channel gene <jats:italic>CACNA1H<\/jats:italic> and childhood absence epilepsy is well established. The purpose of this study was to investigate the range of epilepsy syndromes for which <jats:italic>CACNA1H<\/jats:italic> variants may contribute to the genetic susceptibility architecture and determine the electrophysiological effects of these variants in relation to proposed mechanisms underlying seizures.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Exons 3 to 35 of <jats:italic>CACNA1H<\/jats:italic> were screened for variants in 240 epilepsy patients (167 unrelated) and 95 control subjects by single\u2010stranded conformation analysis followed by direct sequencing. Cascade testing of families was done by sequencing or single\u2010stranded conformation analysis. Selected variants were introduced into the CACNA1H protein by site\u2010directed mutagenesis. Constructs were transiently transfected into human embryo kidney cells, and electrophysiological data were acquired.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>More than 100 variants were detected, including 19 novel variants leading to amino acid changes in subjects with phenotypes including childhood absence, juvenile absence, juvenile myoclonic and myoclonic astatic epilepsies, as well as febrile seizures and temporal lobe epilepsy. Electrophysiological analysis of 11 variants showed that 9 altered channel properties, generally in ways that would be predicted to increase calcium current.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Variants in <jats:italic>CACNA1H<\/jats:italic> that alter channel properties are present in patients with various generalized epilepsy syndromes. We propose that these variants contribute to an individual's susceptibility to epilepsy but are not sufficient to cause epilepsy on their own. The genetic architecture is dominated by rare functional variants; therefore, <jats:italic>CACNA1H<\/jats:italic> would not be easily identified as a susceptibility gene by a genome\u2010wide case\u2013control study seeking a statistical association. Ann Neurol 2007<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.21169","type":"journal-article","created":{"date-parts":[[2007,8,14]],"date-time":"2007-08-14T15:47:43Z","timestamp":1187106463000},"page":"560-568","source":"Crossref","is-referenced-by-count":196,"title":["Extended spectrum of idiopathic generalized epilepsies associated with <i>CACNA1H<\/i> functional variants"],"prefix":"10.1002","volume":"62","author":[{"given":"Sarah E.","family":"Heron","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houman","family":"Khosravani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Varela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Bladen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristiana 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