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Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor\u00a02 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca<jats:sup>2+<\/jats:sup> handling in WT and mutant human\u00a0<jats:italic>RYR2<\/jats:italic> transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca<jats:sup>2+<\/jats:sup> release in response to cytosolic Ca<jats:sup>2+<\/jats:sup> was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca<jats:sup>2+<\/jats:sup> handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.<\/jats:p>","DOI":"10.1038\/s41598-021-84373-9","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T11:04:29Z","timestamp":1614855869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes"],"prefix":"10.1038","volume":"11","author":[{"given":"Zahia","family":"Touat-Hamici","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malorie","family":"Blancard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruifang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianyun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasmine","family":"Iddir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabelle","family":"Denjoy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine","family":"Leenhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiguang","family":"Yuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascale","family":"Guicheney","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"84373_CR1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.3389\/fcvm.2018.00123","volume":"5","author":"G Cheniti","year":"2018","unstructured":"Cheniti, G. et al. 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