TRIO基因变异致常染色体显性遗传性智力发育障碍临床特点及遗传学分析

Clinical features and genetic analysis of autosomal dominant mental retardation caused by TRIO gene mutations

目的:总结TRIO基因变异致2例常染色体显性遗传性智力发育障碍(MRD)患儿的临床表型和基因型特点。方法:回顾性研究郑州大学附属儿童医院神经内科2019年4月、2023年1月确诊的2例TRIO基因变异致常染色体显性MRD患儿的临床资料,总结其临床特征、基因分析及随访情况。结果:2例患儿年龄分别为6岁5个月及5月龄,均为男性,临床表现均有癫痫发作、认知功能及运动障碍,智能发育低下。例1合并有小头畸形、注意力缺陷障碍、共济失调、攻击行为;例2有巨颅畸形。头颅磁共振成像结果提示:例1存在小脑萎缩,例2为非特异性蛛网膜下腔增宽、胼胝体发育不全。2例患儿染色体核型及染色体拷贝数变异分析检查结果均未见异常。全外显子基因测序结果提示其TRIO基因均存在未见报道的新生错义变异[分别为NM_007118:c.4289C>A(p.Thr1430Lys)和c.4111C>A(p.His1371Asn)]。2例患儿经应用康复功能训练及多种抗癫痫发作药物均不能完全有效控制发作。结论:TRIO基因的新生错义变异c.4289C>A(p.Thr1430Lys)、c.4111C>A(p.His1371Asn)为2例患儿的遗传学病因,可导致罕见的常染色体显性MRD44型及63型。

Objective:To summary the clinical phenotype and genotype characteristics of 2 cases of autosomal dominant mental retardation(MRD)caused by TRIO gene variation.Methods:Retrospective study of the clinical data of 2 cases of autosomal dominant MRD caused by TRIO gene mutations diagnosed at the Department of Neurology,Children′s Hospital Affiliated to Zhengzhou University in April 2019 and January 2023 was conducted.The clinical features were summarized and gene analysis and follow-up were carried out.Results:The 2 patients were 6 years and 5 months old and 5 months old males,respectively.Clinical manifestations included seizures,cognitive and motor disorders,low intelligent development;case 1 had microcephaly,attention deficit disorder,ataxia,and aggressive behavior,and case 2 had macrocephaly.Brain magnetic resonance imaging revealed cerebellar atrophy in case 1,and non-specific dilation of the subarachnoid space and hypoplasia of the corpus callosum in case 2.Analysis of chromosome karyotype and chromosome copy number variation in 2 children showed no abnormalities.Whole exome sequencing revealed novel missense mutations in the TRIO gene in both patients[NM_007118:c.4289C>A(p.Thr1430Lys),c.4111C>A(p.His1371Asn),respectively].The application of rehabilitation function training and a variety of anti-seizure medications can not fully and effectively control the seizure.Conclusion:TRIO gene c.4289C>A(p.Thr1430Lys),c.4111C>A(p.His1371Asn)de novo missense variants were the genetic etiology of the 2 probands,causing rare autosomal dominant MRD type 44 and 63.