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The spectrum of pathogenic\n                      <jats:italic>CACNA1E<\/jats:italic>\n                      variants was compared to the mutational landscape of variants in the gnomAD control population database.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in\n                      <jats:italic>CACNA1E<\/jats:italic>\n                      . Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype\u2013phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with\n                      <jats:italic>CACNA1E<\/jats:italic>\n                      variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Limitations<\/jats:title>\n                    <jats:p>The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results indicate that\n                      <jats:italic>CACNA1E<\/jats:italic>\n                      variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene.\n                      <jats:italic>CACNA1E<\/jats:italic>\n                      deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.\n                    <\/jats:p>\n                  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Eur J Med Genet. 2020;63(10):104004.","journal-title":"Eur J Med Genet."}],"container-title":["Molecular Autism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13229-021-00473-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13229-021-00473-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13229-021-00473-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T07:03:12Z","timestamp":1635231792000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularautism.biomedcentral.com\/articles\/10.1186\/s13229-021-00473-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,26]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["473"],"URL":"https:\/\/doi.org\/10.1186\/s13229-021-00473-3","relation":{},"ISSN":["2040-2392"],"issn-type":[{"value":"2040-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,26]]},"assertion":[{"value":"28 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 October 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All subjects provided written informed consent, obtained from their legal guardians, and the study was conducted in adherence with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All subjects consented for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The genetic data supporting the findings of this study, as a whole, contain information that could compromise the privacy and\/or consent of the participants. We therefore only provide the causative variants\u2019 details, which are available in the manuscript and tables.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of data and materials"}}],"article-number":"69"}}