DEPDC5基因变异的癫痫大家系及其中1例携带GABRA1基因新发变异患者的临床遗传学分析

Clinical genetic analysis of a epileptic family with DEPDC5 gene variant and a patient with a de novo variant in the GABRA1 gene

目的报道1个由DEPDC5基因变异引起癫痫发作的大家系,并对该家系中既携带DEPDC5基因变异、又存在GABRA1基因新发变异者进行临床遗传学分析。方法收集于2024年1月就诊于河北省人民医院、存在新发现的DEPDC5基因变异的癫痫大家系的病例资料,抽取该家系成员外周血进行相关遗传检测。针对先证者,运用全外显子组测序技术筛选其致病突变位点。家系中的其他成员采用二代测序技术检测与患者临床表型相关的致病突变位点,并通过一代Sanger测序技术进行验证。结果在幼儿时期癫痫发作且携带2个基因变异位点的先证者,其发病年龄较早,智力及运动发育全面滞后,临床主要表现为局灶性发作、肌阵挛以及强直-阵挛等症状,相较于青春期发病、仅携带1个变异位点,并以全面性癫痫发作及多数伴有注意力缺陷多动障碍的其他家族成员而言,先证者展现出明显的临床异质性。全外显子组测序检测结果提示先证者同时存在GABRA1基因c.640C>T(p.Arg214Cys)新发变异与遗传自其父亲的DEPDC5基因c.4348A>T(p.Lys1450*)变异,其中遗传自其父亲的变异位点为首次发现,之前未曾被报道过。其父的该变异位点遗传自先证者的祖父,先证者的母亲及祖母均不存在该致病突变位点。该家系中5例相似出现癫痫发作表型的患者均存在DEPDC5基因的同一位点致病性突变(c.4348A>T,p.Lys1450*),其余3例出现癫痫发作症状的患者未进行基因检测。结论DEPDC5基因变异为该家系患者的致病原因,c.4348A>T为新发现的变异位点;先证者同时携带GABRA1基因及DEPDC5基因的变异位点。先证者的临床表现与其他家系成员相比具有明显异质性。

ObjectiveTo report a large family of epileptic seizures caused by DEPDC5 gene variation,and to conduct a clinical genetic analysis on a proband in this family with both DEPDC5 gene mutation and a de novo GABRA1 gene mutation.MethodsThe medical records of a family suffering from epilepsy due to a newly identified DEPDC5 gene variant were compiled from cases admitted to Hebei General Hospital in January 2024.The relevant genetic detection was carried out by sampling the peripheral blood of the family members.The whole exome sequencing techniques were employed for the identification of pathogenic mutation sites in the proband.The next generation sequencing technology was utilized for other family members to identify disease-causing mutation sites associated with the clinical phenotype of patients,and these findings were confirmed using first-generation Sanger sequencing technology.ResultsThe proband,who experienced seizures in early childhood and harbored two gene mutation sites,exhibited an early onset age along with significant delays in both intellectual and motor development.The primary clinical manifestations included focal seizures,myoclonus,and tonic-clonic symptoms.When compared with other family members who had the onset of epilepsy during adolescence,carried only one mutation site,and had generalized epileptic seizures and mostly accompanied by attention deficit hyperactivity disorder,the proband showed obvious clinical heterogeneity.The results of whole exome sequencing indicated that the proband had both GABRA1 c.640C>T(p.Arg214Cys)and DEPDC5 c.4348A>T(p.Lys1450*)mutations inherited from the father.The mutation inherited from the father was reported here for the first time and had not been reported before,with the paternal mutation traceable to the proband's grandfather,while the proband's mother and grandmother were found to be devoid of the mutation.In this family,5 patients with similar seizure phenotype all had pathogenic mutations at the same locus of the DEPDC5 gene(c.4348A>T,p.Lys1450*),and the remaining 3 patients with seizure symptoms were not tested.ConclusionsThe DEPDC5 gene mutation is the cause of the disease in this family,and the c.4348A>T is the newly discovered mutation site.The proband carries the mutation sites of both GABRA1 gene and DEPDC5 gene.The clinical manifestations of proband are significantly heterogeneous compared with those of his family members.