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Previous studies have shown a role for genetics in the pathology of task-specific focal dystonia. However, to date, no causal gene has been reported for task-specific focal dystonia, including WC. In this study, we investigated the genetic background of a large Dutch family with autosomal dominant\u2012inherited WC that was negative for mutations in known dystonia genes. Whole exome sequencing identified 4 rare variants of unknown significance that segregated in the family. One candidate gene was selected for follow-up, Calcium Voltage-Gated Channel Subunit Alpha1 H, <jats:italic>CACNA1H,<\/jats:italic> due to its links with the known dystonia gene Potassium Channel Tetramerization Domain Containing 17, <jats:italic>KCTD17,<\/jats:italic> and with paroxysmal movement disorders. Targeted resequencing of <jats:italic>CACNA1H<\/jats:italic> in 82 WC cases identified another rare, putative damaging variant in a familial WC case that did not segregate. Using structural modelling and functional studies in vitro, we show that both the segregating p.Arg481Cys variant and the non-segregating p.Glu1881Lys variant very likely cause structural changes to the Cav3.2 protein and lead to similar gains of function, as seen in an accelerated recovery from inactivation. Both mutant channels are thus available for re-activation earlier, which may lead to an increase in intracellular calcium and increased neuronal excitability. Overall, we conclude that rare functional variants in <jats:italic>CACNA1H<\/jats:italic> need to be interpreted very carefully, and additional studies are needed to prove that the p.Arg481Cys variant is the cause of WC in the large Dutch family.<\/jats:p>","DOI":"10.1186\/s13041-021-00736-3","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T11:04:06Z","timestamp":1611227046000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Rare functional missense variants in CACNA1H: What can we learn from Writer\u2019s cramp?"],"prefix":"10.1186","volume":"14","author":[{"given":"Miaozhen","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther A. 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All in vitro experiments were performed in accordance with the guidelines of the Hotchkiss Brain Institute, University of Calgary (Calgary, Alberta, Canada).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18"}}