SYNGAP1相关智力障碍患儿的临床特征及遗传学分析

Clinical phenotype and genotype characteristics of SYNGAP1-related intellectual disability

目的探讨突触Ras GTP激活蛋白1(synaptic ras GTPase activating protein 1,SYNGAP1)基因变异导致SYNGAP1相关智力障碍患儿的临床表型和分子遗传学特点。方法回顾性总结厦门大学附属妇女儿童医院2014年1月至2021年11月诊治的4例SYNGAP1相关智力障碍患儿的临床资料,分析分子遗传学特点及治疗转归情况。并以“SYNGAP1基因”“精神发育迟滞5型”“SYNGAP1 gene”“autosomal dominant intellectual developmental disorder-5(MRD5)”为检索词,检索Pubmed、中国知网、万方医学网等数据库,选取有SYNGAP1基因变异及相关临床资料的文献进行文献复习。结果本研究中4例和文献检索中6例患儿主要临床表现为中重度的智力障碍、认知障碍、严重语言障碍、行为学障碍、发育迟缓、癫痫及自闭症等;4例移码突变,2例无义突变,2例错义突变,2例剪切突变;头颅MRI检查中5例正常,1例示两侧枕顶叶深部脑室体后部旁白质多发异常信号,1例左侧大脑半球脑沟增宽,轻度脑积水,1例左侧额叶中线旁皮层下及左侧脑室前角旁FLAIR高信号,1例侧脑室轻度扩张,1例左侧脑室增大,右额颞脑沟增深增宽;脑电图2例正常,7例改变包括慢波放电,广泛多棘波、双侧同步或不同步发放尖慢、棘慢、多棘慢综合波、双侧大量高棘-高幅尖慢波,可呈节律性阵发、双侧全导少量极高幅尖慢波节律性阵发、背景波增多等。7例共患癫痫患儿中4例抗癫痫治疗效果差,2例治疗后癫痫发作次数减少,1例文献缺失。结论SYNGAP1相关智力障碍主要表现为智力障碍,运动及语言发育迟缓、癫痫等,抗癫痫治疗效果欠佳,全外显子测序有助于明确诊断,多为新发变异,以移码突变为主。

Objective To investigate the clinical phenotype and genotype characteristics of SYNGAP1-Related Intellectual Disability.Methods The clinical data of 4 children with mental retardation type 5 caused by SYNGAP1 gene mutation who were diagnosed and treated in Department of Pediatrics,Women and Children’s Hospital,School of Medicine,Xiamen University from January 2014 to November 2021 were retrospectively summarized.The literature was retrieved using keywords such as“SYNGAP1 gene”,“SYNGAP1-Related Intellectual Disability”and“autosomal dominant intellectual developmental disorder-5(MRD5)”from the CNKI,VIP database,Wanfang database,Biomedicine Literature database,and Web of Science from the establishment of the databases.Relevant features were examined.Results The main clinical manifestations of the 4 cases in this study and the 6 cases in the literature search were moderate to severe intellectual disability,cognitive impairment,severe language impairment,behavioraldisorder,developmentaldelay,epilepsy and autism,etc.Among them,there were 4 cases of frameshift mutations,2 cases of nonsense mutations,2 cases of missense mutations,and 2 cases of splice mutations.The brain MRI revealed that 5 cases exhibited normal findings,while 1 case demonstrated multiple abnormal signals in the posterior white matter of the bilateral occipital and parietal deep ventricles.Additionally,another case presented with widened cerebral sulci in the left hemisphere along with mild hydrocephalus.Furthermore,one case displayed FLAIR hyperintensity in the subcortex adjacent to the left midline of the frontal lobe and anterior horn of the left ventricle.Moreover,a mild dilatation of the lateral ventricle was observed in one case,whereas another case showed enlargement of both the left ventricle and right frontotemporal sulci.The electroencephalogram(EEG)was within normal limits in 2 cases,while 7 cases exhibited various EEG abnormalities including slow wave discharges,extensive spike waves,bilateral synchronous or asynchronous firing of sharp slow waves,spike slow waves,a significant number of bilateral high-very-high-amplitude sharp slow waves that could be rhythmic bursts,a small amount of bilateral full-conduction rhythmic bursts with extremely high amplitude sharp slow waves,and an increase in background activity.Among the 7 patients with epilepsy,4 exhibited inadequate response to antiepileptic therapy,while 2 demonstrated a decrease in seizure frequency following treatment.Conclusions The primary clinical manifestations of Syngap1-related intellectual disability include cognitive impairment,delayed motor and language development,andepilepsy.However,conventional anti-epileptic treatment has shown limited efficacy.Whole exome sequencing can significantly aid in the accurate diagnosis of this disorder.The majority of the mutations observed were de novo,predominantly consisting of frameshift mutations.