GRIN2A基因变异所致癫痫失语疾病谱临床表型及基因型分析

Analysis of the clinical presentation and genetic profile of epilepsy-aphasia spectrum due to GRIN2A gene mutations

目的探讨经二代测序确诊的GRIN2A基因变异所致癫痫失语疾病谱患儿的临床表型特征及基因变异特点。方法回顾性分析2019年2月至2022年11月郑州大学附属儿童医院神经内科确诊的5例以癫痫起病的癫痫失语疾病谱患儿的临床资料,采用二代测序方法对先证者进行全外显子基因组测序,证实5例均为GRIN2A基因变异患儿,并通过一代Sanger测序对家系成员进行验证以确认变异来源,对GRIN2A基因变异特点进行分析。结果5例确诊为GRIN2A基因变异所致癫痫失语疾病谱的患儿中,男女比例为4∶1,起病年龄范围为1.5~4.4岁。临床表型均有癫痫发作,4例有语言及智能发育落后;3例共患有注意力缺陷多动障碍;癫痫发作表现为局灶性发作或继发全面性发作;应用抗癫痫药物均得到有效控制。5例患儿中例1的基因变异源于父亲杂合变异,例2~5均为新发变异,分别为c.2107C>T(p.Gln703*)无义变异、c.2284G>A(p.Gly762Arg)错义变异、c.2197del(p.Ala733Glnfs*3)移码变异、c.2511G>A(p.Trp837*)无义变异、c.1651+1G>C剪切位点变异。经查阅文献,5例的基因变异位点均未见相关报道。结论癫痫失语疾病谱是一种起病复杂的癫痫综合征,不同基因变异位点可能有不同表型,发作形式以局灶性发作为主,部分可继发全面性发作,应用抗癫痫药物能够有效控制发作。GRIN2A基因变异为癫痫失语疾病谱的遗传学病因。

Objective To explore the clinical phenotypic features and genetic variation characteristics of children with epilepsy-aphasia spectrum due to GRIN2A gene variants confirmed by second-generation sequencing.Methods The clinical data of 5 children with epilepsy-aphasia spectrum with epileptic onset diagnosed in the Department of Neurology,Children's Hospital Affiliated to Zhengzhou University,from February 2019 to November 2022 were retrospectively analyzed.Whole-exome genome sequencing of the probands using a second-generation sequencing method confirmed that all 5 cases were children with the GRIN2A gene variant.The characteristics of the GRIN2A gene variants were analyzed.Results Among the 5 children diagnosed with epileptic aphasia spectrum due to GRIN2A gene variants,the male-to-female ratio was 4∶1,and the age range of onset was 1.5-4.4 years.The clinical phenotype included seizures in all cases,language and intellectual developmental deficits in 4 cases,and attention deficit hyperactivity disorder in 3 cases.The seizures were manifested as focal seizures or secondary generalized seizures,and were effectively controlled with antiepileptic drugs.Among the 5 children,gene variant of case 1 was originated from a paternal heterozygous variant,and cases 2-5 had de novo variants,which were c.2107C>T(p.Gln703*)nonsense variant,c.2284G>A(p.Gly762Arg)missense variant,c.2197del(p.Ala733Glnfs*3)shifted coding variant,c.2511G>A(p.Trp837*)nonsense variant,and c.1651+1G>C shear site variant,respectively.None of the 5 loci were reported in the literature.Conclusions Epilepsy-aphasia spectrum is an epilepsy syndrome with a complex onset,and may have different phenotypes at different genetic variant loci,with focal seizures or secondary generalized seizures,which can be effectively controlled with anti-seizure medication.The GRIN2A gene variant is the genetic etiology of the epileptic aphasia spectrum.