BACKGROUND The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. METHODS A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. RESULTS Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28-174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. CONCLUSIONS A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

中文翻译：

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具有SYNGAP1致病变异的个体的表型特征揭示了后显性节律与发育进程之间的潜在相关性。

背景SYNGAP1基因编码小的GTPase调节蛋白，对树突棘的成熟和突触可塑性至关重要。最近发现突变会引起广泛的神经发育障碍，包括自闭症，智力障碍和癫痫病。这项工作的目的是定义SYNGAP1基因突变的表型谱，并确定临床严重程度和发展进程的潜在生物标志物。方法对SYNGAP1突变个体进行回顾性临床资料分析。数据包括遗传诊断，临床病史和检查，神经生理学数据，神经影像学以及系列神经发育/行为评估。在6年内纵向看过所有患者。数据分析已于2018年6月30日完成。审查了所有被诊断为有害SYNGAP1变异的个体的记录（通过临床测序或外显子组测序）。结果据报道有15个人（53％的男性）具有17个独特的SYNGAP1突变。基因诊断的平均年龄为65.9个月（28-174个月）。所有个体均患有癫痫病，非典型性癫痫发作是最常见的符号学（60％）。脑电图异常包括间歇性节律性三角肌活动（60％），后部显性节奏缓慢或不存在（87％）和癫痫样活动（93％），广泛性放电比局灶性放电更为常见。神经影像学检查显示非特异性异常（53％）。神经发育评估显示所有个体均受损，总体运动功能受影响最小。诊断为自闭症谱系障碍的占73％，具有攻击性的占60％。对生物标志物的分析显示，视觉-感知/精细运动/适应能力与语言发展之间呈适度正相关的趋势，而脑电图（EEG）具有后显性节律，与年龄无关。未发现其他神经生理学发展关联或相关性。结论发现SYNGAP1的致病性变异具有广泛的神经系统和神经发育特征。脑电图的后部显性节律异常与发育进展异常相关，提供了可能的预后生物标志物。脑电图（EEG）的后显性主导节律，与年龄无关。未发现其他神经生理学发展关联或相关性。结论发现SYNGAP1的致病性变异具有广泛的神经和神经发育特征。脑电图的后部显性节律异常与发育进展异常相关，提供了可能的预后生物标志物。脑电图（EEG）的后显性主导节律，与年龄无关。未发现其他神经生理学发展关联或相关性。结论发现SYNGAP1的致病性变异具有广泛的神经和神经发育特征。脑电图的后部显性节律异常与发育进展异常相关，提供了可能的预后生物标志物。