摘要
目的探讨3例PRRT2基因变异所致发作性运动诱发性运动障碍(PKD)与自限性家族性婴儿癫痫(SeLIE)患儿的临床表型及遗传学特点。方法选取2022年11月至2023年8月于郑州大学第一附属医院就诊的3例PRRT2基因变异所致PKD与SeLIE患儿(患儿1~3)作为研究对象。采用回顾性研究方法, 收集3例患儿的临床及家族史资料。采集患儿1~3及患儿1~2父母外周静脉血各2 mL(患儿3父母拒绝进行基因检测, 未采集血样), 提取基因组DNA, 进行全外显子组测序(WES), 并采用Sanger测序法进行验证。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南"), 对3例患儿检出的变异位点进行致病性评级, 并应用多重生物信息学软件对变异位点有害性进行分析。本研究已通过郑州大学第一附属医院伦理委员会的审查(批准号:2024-KY-0881-002)。结果本研究3例患儿临床资料及基因检测结果如下。①患儿1:女性, 发病年龄为4个月10 d, 具有癫痫发作, 具体表现为动作突然停止、双眼凝视、口唇发绀、面色苍白, 四肢强直抖动。基因检测结果显示, 患儿1存在母源PRRT2基因c.583584dup(p.P196Afs*34)移码变异, 根据ACMG指南, 被评为致病性变异(PVS1+PM2Supporting+PP4)。根据患儿1临床表现及基因检测结果, 被确诊为SeLIE, 采取口服丙戊酸钠0.5 mL/(kg.d), 至2岁随访时仍在服药中, 5个月龄后未再出现癫痫发作。②患儿2:男性, 发病年龄为10岁, 表现为突然运动后出现肌张力障碍。基因检测结果显示, 患儿2存在PRRT2基因变异:父源c.649dupC(p.R217Pfs*8)移码变异与母源c.445C>A(p.Q149K)变异。其中, c.649dupC为已报道的致病性变异;根据ACMG指南, c.445C>A变异被评为临床意义未明变异(PM2Supporting), 良性可能性大。根据患儿2临床表现及基因检测结果, 被确诊为PKD, 采取口服奥卡西平9 mg/(kg.d)治疗随访至12岁2个月仍在服药中, 服药后未再出现运动障碍形式的发作。③患儿3:男性, 发病年龄为11岁, 表现为突然运动后出现肌张力障碍。基因检测结果显示, 患儿3存在PRRT2基因c.904G>C(p.D302H)错义变异, 其父母拒绝基因检测, 变异来源未知, 根据ACMG指南, 该变异被评为临床意义未明变异(PM2Supporting+PP3Moderate+PP4)。根据患儿3临床表现及基因检测结果, 被确诊为PKD, 采取口服奥卡西平10 mg/(kg.d)治疗1年后自行停药, 17岁时随访, 服药后未再出现运动障碍形式的发作。结论 PRRT2基因变异所致1例SeLIE患儿与2例PKD, 对抗癫痫发作药物反应良好。本研究发现PRRT2基因4种变异位点:c.583584dup、c.904G>C、c.649dupC、c.445C>A, 其中c.583584dup为新变异, 丰富了PRRT2基因变异谱。
Objective To investigate the clinical phenotypic and genetic characteristics of three children with Paroxysmal kinesigenic dyskinesia(PKD)and Self-limited familial infantile epilepsy(SeLIE)caused by PRRT2 gene mutation.Methods Three children with PKD and SeLIE caused by PRRT2 gene mutation(children 1-3)who were treated in the First Affiliated Hospital of Zhengzhou University from November 2022 to August 2023 were selected as the research subjects.A retrospective study was conducted to collect the clinical and family history data of the three children.2 mL of peripheral venous blood from children 1-3 and parents of children 1-2 were collected(parents of children refused to undergo genetic testing and no blood samples were collected),genomic DNA was extracted,whole exome sequencing(WES)was performed,and Sanger sequencing method was used for verification.According to the Classification Standards and Guidelines for Genetic Variants formulated by the American Society of Medical Genetics and Genomics(ACMG)(hereinafter referred to as the"ACMG Guidelines"),the pathogenicity of the variant loci detected in three children was rated,and the detrimental loci of the variant loci were analyzed by multiple bioinformatics software.This study has been approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University(Ethics No.2024-KY-0881-002).Results The clinical data and genetic test results of the three children in this study are as follows.Child l:female,age of onset of 4 months and 1o days,with seizures,manifested as sudden cessation of movements,staring in both eyes,cyanosis of the lips,paleness,and stiffness and shaking of limbs.The results of genetic testing showed that child 1 had maternal PRRT2 gene c.583_584dup(p.P196Afs*34)frameshift variant,which was rated as a pathogenic variant(PVS1 PM2_Supporting PP4)according to ACMG guidelines.According to the clinical manifestations and genetic test results of child l,he was diagnosed with SeLIE and took oral sodium valproate[0.5 mL/(kg.d)],and was still taking medication at the follow-up of 2 years old,and did not have seizures again after 5 months of age.@Child 2:male,age of onset of 10 years old,manifested as dystonia after sudden movement.The results of genetic testing showed that child 2 had PRRT2 gene mutations:paternal c.649dupC(p.R217Pfs*8)frameshift variant and maternal c.445C>A(p.Q149K)mutation.Among them,c.649dupC was a reported pathogenic variant,and according to ACMG guidelines,c.445C>A variant was rated as a variant of unknown clinical significance(PM2_Supporting),with a high probability of benignness.According to the clinical manifestations and genetic test results of the child 2,he was diagnosed with PKD,and was followed up with oral oxcarbazepine 9 mg/(kg.d)until 12 years and 2 months,and was still on the drug,and there was no recurrence of the seizure of the form of dyskinesia after taking the drug.Child 3:male,age of onset of 1l years old,manifested by dystonia after sudden exercise.The results of genetic testing showed that child 3 had a missense variant of PRRT2 gene c.904G>C(p.D302H),and his parents refused genetic testing,and the source of the mutation was unknown,and the variant was rated as a variant of unknown clinical significance(PM2_Supporting+PP3_Moderate+PP4)according to ACMG guidelines.According to the clinical manifestations and genetic test results of child 3,he was diagnosed with PKD,and was treated with oral oxcarbazepine 10 mg/(kg.d)for 1 year and then discontinued on his own,and was followed up at the age of 17,and there was no recurrence of the seizure of the form of movement disorder after taking the drug.Conclusion One case of SeLIE and two cases of PKD caused by PRRT2 gene mutations responded well to anti-seizure drugs.In this study,four variant loci of PRRT2 gene were found:c.583_584dup,c.904G>C,c.649dupC,c.445C>A,among which c.583_584dup were new variants,enriching the variant spectrum of PRRT2 gene.
作者
宋丹丹
彭晓艺
王瑶
蔡奥捷
Sapana Tamang
王怀立
禚志红
Song Dandan;Peng Xiaoyi;Wang Yao;Cai Aojie;Sapana Tamang;Wang Huaili;Zhuo Zhihong(Department of Pediatrics,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450020,China;PICU,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450020,China)
出处
《中华医学遗传学杂志》
2025年第3期292-299,共8页
Chinese Journal of Medical Genetics
基金
河南省科技攻关省部共建重点项目(SBGJ202002054、SBGJ202102109)
郑州市协同创新项目(XTCX2023002)。
