Abstract
Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G > A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).
Highlights
Previous studies have shown that the brain-specific synaptic guanosine triphosphatase (GTPase) activating protein (SynGAP) is important for synaptic plasticity
Six patients were of Han ethnicity and one patient was of Tujia ethnicity (Patient 2)
We described phenotypes in patients with synaptic Ras GTPase activating protein 1 (SYNGAP1) gene mutations, which were characterized by intellectual disability, epilepsy, autism spectrum disorder (ASD), and behavioral problems
Summary
Previous studies have shown that the brain-specific synaptic guanosine triphosphatase (GTPase) activating protein (SynGAP) is important for synaptic plasticity. The synaptic Ras GTPase activating protein 1 (SYNGAP1) gene (MIM:603384) is located on chromosome 6p21.3. The protein encoded is SynGAP, including Ras and Rap GTPases. The mutation of the SYNGAP1 gene can lead to an imbalance of excitement and inhibition in the central nervous system, which affects the formation of synapses during learning and memorizing (Nakajima et al, 2019; Araki et al, 2020). The loss of function of the SYNGAP1 gene has been linked to a variety of neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. MRD5 has a reported incidence of one to four people in 10,000. MRD5 is believed to be the leading cause of ID
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