{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:38:42Z","timestamp":1780515522542,"version":"3.54.1"},"reference-count":19,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014215","name":"Huxiang Youth Talent Support Program","doi-asserted-by":"publisher","award":["2021RC3117"],"award-info":[{"award-number":["2021RC3117"]}],"id":[{"id":"10.13039\/501100014215","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171453"],"award-info":[{"award-number":["82171453"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671297"],"award-info":[{"award-number":["81671297"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of\u00a0Hunan Province","doi-asserted-by":"publisher","award":["2021JJ30393"],"award-info":[{"award-number":["2021JJ30393"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2022,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The <jats:italic>ARHGEF9<\/jats:italic> gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype\u2013phenotype relationship is still unpredictable.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical data of the patients and their family members were gathered in a retrospective study. The exome sequencing that was performed on peripheral blood samples was applied for genetic analysis. We used the <jats:italic>ARHGEF9<\/jats:italic> gene as a key word to search the PubMed database for cases of <jats:italic>ARHGEF9<\/jats:italic> gene variants that have previously been reported and summarized the reported <jats:italic>ARHGEF9<\/jats:italic> gene variant sites, their corresponding clinical phenotypes, and effective treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We described five patients with developmental and epileptic encephalopathy caused by <jats:italic>ARHGEF9<\/jats:italic> gene variants. Among them, the antiepileptic treatment of valproic acid and levetiracetam was effective in two cases individually. The exome sequencing results showed five children with point mutations in the <jats:italic>ARHGEF9<\/jats:italic> gene: p.R365H, p.M388V, p.D213E, and p.R63H. So far, a total of 40 children with <jats:italic>ARHGEF9<\/jats:italic> gene variants have been reported. Their main clinical phenotypes include developmental delay, epilepsy, epileptic encephalopathy, and autism spectrum disorders. The variants reported in the literature, including 22 de novo variants, nine maternal variants, and one unknown variant. There were 20 variants associated with epileptic phenotypes, of which six variants are effective for valproic acid treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The genotypes and phenotypes of <jats:italic>ARHGEF9<\/jats:italic> gene variants represent a wide spectrum, and the clinical phenotype of epilepsy is often refractory and the prognosis is poor. The p.R365H, p.M388V, p.D213E, and p.R63H variants have not been reported in the current literature, and our study has expanded the genotype spectrum of <jats:italic>ARHGEF9<\/jats:italic> gene. Our findings indicate that levetiracetam and valproic acid can effectively control seizures in children with epileptic phenotype caused by <jats:italic>ARGHEF9<\/jats:italic> gene variations. These findings will help clinicians improve the level of diagnosis and treatment of the genetic disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1967","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T09:44:36Z","timestamp":1653990276000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<i>ARHGEF9<\/i> gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1164-8788","authenticated-orcid":false,"given":"Haiyan","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurology Hunan Children's Hospital  Changsha P.R. 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