Department of Neurology, Hunan Children's Hospital, Changsha, P.R. China.
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, P.R. China.
Mol Genet Genomic Med. 2022 Jul;10(7):e1967. doi: 10.1002/mgg3.1967. Epub 2022 May 31.
The ARHGEF9 gene variants have phenotypic heterogeneity, the number of reported clinical cases are limited and the genotype-phenotype relationship is still unpredictable.
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.
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.
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.
ARHGEF9 基因突变具有表型异质性，报道的临床病例数量有限，基因型-表型关系仍难以预测。
在回顾性研究中收集了患者及其家属的临床数据。对外周血样本进行外显子组测序进行基因分析。我们以 ARHGEF9 基因为关键词，在 PubMed 数据库中搜索先前报道的 ARHGEF9 基因突变病例，并总结了报道的 ARHGEF9 基因突变位点、相应的临床表型和有效治疗方法。
我们描述了 5 例由 ARHGEF9 基因突变引起的发育性和癫痫性脑病患者。其中，2 例患者分别使用丙戊酸和左乙拉西坦的抗癫痫治疗有效。外显子组测序结果显示，这 5 例患儿 ARHGEF9 基因均存在点突变：p.R365H、p.M388V、p.D213E 和 p.R63H。迄今为止，共报道了 40 例 ARHGEF9 基因突变患儿。他们的主要临床表型包括发育迟缓、癫痫、癫痫性脑病和自闭症谱系障碍。文献报道的变异包括 22 个新生变异、9 个母体变异和 1 个未知变异。有 20 个变异与癫痫表型相关，其中 6 个变异对丙戊酸治疗有效。
ARHGEF9 基因突变的基因型和表型表现出广泛的谱，癫痫的临床表型通常难治且预后不良。p.R365H、p.M388V、p.D213E 和 p.R63H 变异尚未在当前文献中报道，本研究扩展了 ARHGEF9 基因突变的基因型谱。我们的研究结果表明，左乙拉西坦和丙戊酸可有效控制 ARGHEF9 基因突变引起的癫痫患儿的癫痫发作。这些发现将有助于临床医生提高对遗传性疾病的诊断和治疗水平。
