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Objective:To analyze the clinical characteristics and genetic variation of 2 children with developmental and epileptic encephalopathy 8 (DEE8).Methods:Whole-exome sequencing (WES) was performed to determine the potential variants in the probands. Candidate variants identified by WES were validated by Sanger sequencing and quantitative real-time polymerase chain reaction. X chromosome inactivation (XCI) detection was performed in the proband 1′s mother and proband 2 to detect the allelic expression difference of ARHGEF9. Results:Both of the cases showed global developmental delay. Proband 1 presented with delayed motor and speech development, intellectual disability, and seizures. Electroencephalography of proband 1 showed slow background activity, with spikes, spike and waves in bilateral frontal and midline regions during sleep. While proband 2 showed delay in acquisition of language, motor skills, and cognition, but no seizures. It was identified that proband 1 carried a novel maternally derived heterozygous splicing variant (c.925-2A>T) in ARHGEF9 by WES, which was verified in Sanger sequencing. The XCI in proband 1′s mother was observed, and the expression ratio of mutant ARHGEF9 and wild-type was 0∶100%. A novel exon 3-10 heterozygous deletion of ARHGEF9 was identified in proband 2, and this variant was not found in his unaffected parents. Conclusions:DEE8 disorders are relatively rare. Most of the patients have varying degrees of neurodevelopmental phenotype, but epilepsy is not a specific clinical manifestation. ARHGEF9 gene deletion and splicing variation may be the genetic cause of the 2 probands, and above findings have enriched the spectrum of variation and phenotype of DEE8.
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BACKGROUND: The ARHGEF9 gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype-phenotype relationship is still unpredictable. METHODS: 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 ARHGEF9 gene as a key word to search the PubMed database for cases of ARHGEF9 gene variants that have previously been reported and summarized the reported ARHGEF9 gene variant sites, their corresponding clinical phenotypes, and effective treatment. RESULTS: We described five patients with developmental and epileptic encephalopathy caused by ARHGEF9 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 ARHGEF9 gene: p.R365H, p.M388V, p.D213E, and p.R63H. So far, a total of 40 children with ARHGEF9 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. CONCLUSION: The genotypes and phenotypes of ARHGEF9 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 ARHGEF9 gene. Our findings indicate that levetiracetam and valproic acid can effectively control seizures in children with epileptic phenotype caused by ARGHEF9 gene variations. These findings will help clinicians improve the level of diagnosis and treatment of the genetic disease.
