{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T19:51:29Z","timestamp":1765828289058,"version":"3.40.5"},"reference-count":14,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T00:00:00Z","timestamp":1683936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2023,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Loss of function variants in <jats:italic>CACNA1A<\/jats:italic> cause a broad spectrum of neurological disorders, including episodic ataxia, congenital or progressive ataxias, epileptic manifestations or developmental delay. Variants located on the AG\/GT consensus splice sites are usually considered as responsible of splicing defects, but exonic or intronic variants located outside of the consensus splice site can also lead to abnormal splicing. We investigated the putative consequences on splicing of 11 <jats:italic>CACNA1A<\/jats:italic> variants of unknown significance (VUS) identified in patients with episodic ataxia or congenital ataxia. In silico splice predictions were performed and RNA obtained from fibroblasts was analyzed by Sanger sequencing. The presence of abnormal transcripts was confirmed in 10\/11 patients, nine of them were considered as deleterious and one remained of unknown significance. Targeted next\u2010generation RNA sequencing was done in a second step to compare the two methods. This method was successful to obtain the full cDNA sequence of <jats:italic>CACNA1A<\/jats:italic>. Despite the presence of several isoforms in the fibroblastic cells, it detected most of the abnormally spliced transcripts. In conclusion, RNA sequencing was efficient to confirm the pathogenicity of nine novel <jats:italic>CACNA1A<\/jats:italic> variants. Sanger or Next generation methods can be used depending on the facilities and organization of the laboratories.<\/jats:p>","DOI":"10.1111\/cge.14358","type":"journal-article","created":{"date-parts":[[2023,5,13]],"date-time":"2023-05-13T08:28:25Z","timestamp":1683966505000},"page":"365-370","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of novel <scp><i>CACNA1A<\/i><\/scp> splice variants by <scp>RNA<\/scp>\u2010sequencing in patients with episodic or congenital ataxia"],"prefix":"10.1111","volume":"104","author":[{"given":"Florence","family":"Riant","sequence":"first","affiliation":[{"name":"AP\u2010HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydie","family":"Burglen","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique et Embryologie M\u00e9dicale APHP, Sorbonne Universit\u00e9, Centre de R\u00e9f\u00e9rence Malformations et Maladies Cong\u00e9nitales du Cervelet, H\u00f4pital Trousseau  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaelle","family":"Corpechot","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julien","family":"Robert","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Durr","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, Paris Brain Institute (ICM Institut du Cerveau), INSERM, CNRS, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP)  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guilhem","family":"Sol\u00e9","sequence":"additional","affiliation":[{"name":"Service de Neurologie, Unit\u00e9 Neuromusculaire, CHU de Bordeaux \u2013 H\u00f4pital Pellegrin  Bordeaux France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-1023","authenticated-orcid":false,"given":"Florence","family":"Petit","sequence":"additional","affiliation":[{"name":"CHU Lille, Clinique de G\u00e9n\u00e9tique Guy Fontaine  Lille France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9cile","family":"Freihuber","sequence":"additional","affiliation":[{"name":"Service de Neurop\u00e9diatrie, APHP, H\u00f4pital Trousseau  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"De Marco","sequence":"additional","affiliation":[{"name":"Service de Neurologie, H\u00f4pital de La Roche sur Yon  La Roche sur Yon France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"Sarret","sequence":"additional","affiliation":[{"name":"Service de P\u00e9diatrie, H\u00f4pital Estaing, Centre Hospitalier Universitaire de Clermont\u2010Ferrand  Clermont\u2010Ferrand France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Castelnovo","sequence":"additional","affiliation":[{"name":"Service de Neurologie, CHU N\u00eemes, H\u00f4pital Caremeau  N\u00eemes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fran\u00e7oise","family":"Devillard","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique et Procr\u00e9ation H\u00f4pital Couple\u2010Enfant, CHU de Grenoble  Grenoble France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Afenjar","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique et Embryologie M\u00e9dicale APHP, Sorbonne Universit\u00e9, Centre de R\u00e9f\u00e9rence Malformations et Maladies Cong\u00e9nitales du Cervelet, H\u00f4pital Trousseau  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B\u00e9n\u00e9dicte","family":"H\u00e9ron","sequence":"additional","affiliation":[{"name":"Service de Neurop\u00e9diatrie, APHP, H\u00f4pital Trousseau  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth Tournier","family":"Lasserve","sequence":"additional","affiliation":[{"name":"AP\u2010HP, Service de G\u00e9n\u00e9tique Mol\u00e9culaire Neurovasculaire, H\u00f4pital Saint\u2010Louis  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,5,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81373-2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm126"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx081"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-020-02396-z"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2022.860662"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14985"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2016.11.005"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2016-314863"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.14261"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24491"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.21"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37678"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-021-00919-5"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14358","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T12:59:50Z","timestamp":1692277190000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14358"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,13]]},"references-count":14,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,9]]}},"alternative-id":["10.1111\/cge.14358"],"URL":"https:\/\/doi.org\/10.1111\/cge.14358","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"type":"print","value":"0009-9163"},{"type":"electronic","value":"1399-0004"}],"subject":[],"published":{"date-parts":[[2023,5,13]]},"assertion":[{"value":"2023-03-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}