{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:12:39Z","timestamp":1791922359987,"version":"4.3.4"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T00:00:00Z","timestamp":1656201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["5T35AG044303\u201009"],"award-info":[{"award-number":["5T35AG044303\u201009"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Pathogenic variants in the\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    gene have been associated with episodic ataxia type 2, familial hemiplegic migraine, and spinocerebellar ataxia 6. With increasing use of clinical genetic testing, associations have expanded to include developmental delay, epilepsy, paroxysmal dystonia, and neuropsychiatric disorders. We report 47 individuals with 33 unique likely pathogenic or pathogenic\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    variants. A machine learning method, funNCion, was used to predict loss\u2010of\u2010function (LoF)\/gain\u2010of\u2010function (GoF) impact of genetic variants, and a heuristic severity score was designed to analyze genotype\/phenotype correlations. Commonly reported phenotypes include developmental delay\/intellectual disability (96%), hemiplegic migraines (36%), episodic ataxia type 2 (32%), epilepsy (55%), autism spectrum disorder (23%), and paroxysmal tonic upward gaze (36%). Severity score was significantly higher for predicted GoF variants, variants in the S5\/S6 helices, and the recurrent p.Val1392Met variant. Seizures\/status epilepticus were correlated with GoF and were more frequent in those with the p.Val1392Met variant. Our findings demonstrate a breadth of disease severity in\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    \u2010related disease and suggest that the clinical phenotypic heterogeneity likely reflects diverse molecular phenotypes. A better understanding of the natural history of\n                    <jats:italic>CACNA1A<\/jats:italic>\n                    \u2010related disease and genotype\/phenotype correlations will help inform prognosis and prepare for future clinical trials.\n                  <\/jats:p>","DOI":"10.1111\/cge.14180","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T04:41:58Z","timestamp":1655700118000},"page":"288-295","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Clinical and genetic characterization of\n                    <scp>\n                      <i>CACNA1A<\/i>\n                    <\/scp>\n                    \u2010related disease"],"prefix":"10.1111","volume":"102","author":[{"given":"Amy R.","family":"Lipman","sequence":"first","affiliation":[{"name":"Vagelos College of Physicians and Surgeons  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Columbia University  New York New York USA"},{"name":"Department of Systems Biology Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology Columbia University  New York New York USA"},{"name":"Department of Biomedical Informatics Columbia University  New York New York USA"},{"name":"JP Sulzberger Columbia Genome Center Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Columbia University  New York New York USA"},{"name":"Department of Medicine Columbia University  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,26]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.639994"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(00)81373\u20102"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0197\u201062"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.21"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2021.05.010"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2020.10.004"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2019.00329"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2010.01.010"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22911"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13040\u2010017\u20100126\u20108"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3477"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1101\/2021.04.22.441037"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay6848"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006905"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.06.003"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2454\u201012.2012"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2014.10.005"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2009.177279"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.1031"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1159\/000512275"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201002554\u2010x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00247.2005"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.07.014"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2018.08.011"}],"container-title":["Clinical 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