关键词: Nicolaides-Baraitser综合征, SMARCA2基因, 癫痫, 发育落后, 智力障碍

Abstract: Background: SMARCA2 gene mutations can lead to different neurodevelopmental disorders. Objective: To summarize the clinical and genetic characteristics of SMARCA2 related disorders. Design: Case Series Report. Methods: Cases were enrolled who met the following inclusion criteria: aged 0-18 years who were included in the databases of Clinical Big Data of Children with Mental Disorders/Developmental Delays and Clinical Big Data of Children with Epilepsy in the Department of Pediatrics, Xiangya Hospital, Central South University from January 2017 to December 2021; the genetic test results showed that the SMARCA2 gene mutation was pathogenic or likely pathogenic; there were follow-up records after the first visit. Children's demography information, maternal pregnancy history, birth history and past history, seizure types and frequency, anti-seizure medications, physical examination, EEG, growth and development assessment data were collected. The last follow-up was January 2022. Based on previous literature reports, the clinical and genetic characteristics of SMARCA2 related diseases were summarized. Main outcome measures: Frequency of epileptic seizures. Results: Among the 6 cases of SMARCA2 related nervous system disease, 3 cases were male and 3 cases were female. Case 6 was diagnosed as Lennox-Gastaut syndrome(LGS), and case 1-5 were diagnosed as Nicolaides-Baraitser syndrome(NCBRS). The follow-up period was 1.75 (0.58-3.25) years. They all denied any previous history of heat shock, other intracranial lesions, or similar family history. All had varying degrees of developmental delay. The median onset age of seizure was 9 (8-19)months. In case 6, seizures manifested as spasms, tonic spasm, atypical absence seizure and myoclonus seizure. In cases 1-5, there were four instances of generalized tonic-clonic seizures, three instances of focal seizures, two instances of spasms, two instances of cluster seizures, and one instance of status epilepticus. All five cases exhibited distinct facial characteristics, such as a triangular face, prominent eyelashes, broad nasal base, and broad philtrum. Additionally, they all presented with stunted growth and microcephaly. In contrast, case six only displayed a broad nasal base. Six cases were treated with antiepileptic drugs such as sodium valproate, adrenocorticotropin, chlorhexidine, and levetiracetam. The seizures were completely controlled in two cases, and significant improvement was observed in four cases. All were detected with SMARCA2 (NM_003070) de novo heterozygous missense mutation. The missense mutations were located in the ATPase/C-terminal Helicase domain in cases 1 to 5, and were in HSA domain in case 6. The missense variation in cases 1 to 6 is: c.2554G>A/pathogenic, c.2564G>A/pathogenic, c.3394G>A/pathogenic, c.2551G>A/pathogenic, c.2830C>A/likely pathogenic, c.1399C>T/likely pathogenic. Cases 3-6 have not been reported. Conclusions: The SMARCA2 gene mutation can lead to neurodevelopmental disorders with NCBRS as the main phenotype. There are genotype-phenotype associations in SMARCA2 related neurodevelopmental disorders. The common features including developmental delay/intellectual disability and epilepsy. Children with NCBRS also have special rough facial features and developmental abnormalities, and prominent language deficits.

Key words: Nicolaides-Baraitser syndrome, SMARCA2 gene, Epilepsy, Developmental Delay, Intellectual disability