SYNGAP1基因变异患儿的早期神经发育表型与基因型的相关性

Correlation of early neurodevelopmental features of children with SYNGAP1 variants and their genotypes

目的探讨SYNGAP1基因变异患儿的早期智力发育障碍表型,并确定其基因型与表型的相关性。方法将2019年1月至2022年7月就诊于首都儿科研究所附属儿童医院、通过全外显子组测序检出SYNGAP1基因变异的幼儿(<5岁)作为研究对象。所有患儿均完成了儿童神经心理发育评估、家系验证和基因变异的致病性评估。在文献中检索携带SYNGAP1基因致病/可能致病变异的小年龄段幼儿(<5岁),必须有详细表型、0~6岁神经心理发育量表或其他神经心理发育状态评估数值,作为SYNGAP1基因变异患儿的早期神经发育表型特点,之后分析其表型特点与基因型的相关性。结果共纳入4例携带SYNGAP1基因可能致病/致病变异的患儿(1男3女,平均年龄为34.0±18.2个月),其中1例携带既往未见报道的变异(c.437C>G,p.S146*)。文献检索共发现19例患儿。在23例携带SYNGAP1基因变异的患儿(8男10女,5名性别未知,年龄为37.1±14.2个月)中,19例(82.6%)为功能丧失变异。所有患儿均在2岁前出现全面发育迟缓,有16例(69.6%)出现惊厥/癫痫发作,发病年龄为27.0±12.1个月,其中15例的惊厥/癫痫出现在发育迟缓之后,提示早期全面发育迟缓并非惊厥/癫痫引起。肌阵挛发作和失神发作是其常见的发作类型。与携带第8~15外显子变异者相比,第1~5外显子变异者发育迟缓严重程度较轻。结论携带SYNGAP1基因变异的小年龄患者主要表现为全面发育迟缓和癫痫,在2岁前即出现发育迟缓,其严重程度可能与变异类型和所在的外显子有关。

Objective To explore the early neurodevelopmental features of young children with SYNGAP1 variants and their genotype-phenotype correlation.Methods Young children with neurodevelopmental disorders(NDDs)(<5 years old)who were referred to the Children′s Hospital Affiliated to the Capital Institute of Pediatrics between January 2019 and July 2022 were selected as the study subjects.All children had undergone whole-exome sequencing,comprehensive pediatric neuropsychological assessment,familial segregation analysis,and pathogenicity classification.Meanwhile,young Chinese NDD children(<5 years old)with pathogenic/likely pathogenic SYNGAP1 variants were retrieved from the literature,with information including detailed clinical and genetic testing,neurodevelopmental quotient(DQ)of the Children Neuropsychological and Behavior Scale-Revision 2016(CNBS-R2016).Children who did not have a detailed DQ but had their developmental status assessed by a medical professional were also included.The correlation between neurodevelopmental severity,comorbidity and SYNGAP1 variants were summarized.Results Four young NDD children carrying SYNGAP1 variants were recruited(1 male and 3 females,with a mean age of 34.0±18.2 months),among whom one harboring a novel variant(c.437C>G,p.S146*).Combined with 19 similar cases retrieved from the literature,23 Chinese NDD young children were included in our study(8 males and 10 females,5 with unknown sex,with a mean age of 37.1±14.2 months).A loss of function(LOF)variant was found in 19(82.6%)children.All of the children had presented global developmental delay(GDD)before the age of two.In addition,16(69.6%)had seizure/epilepsy at the age of 27.0±12.1 months,among whom 15 had occurred independent of the global developmental delay.Myoclonic and absence were common types of seizures.Compared with those with variants of exons 8 to 15,the severity of developmental delay was milder among children with variants in exons 1 to 5.Conclusion The early neurodevelopment features of the SYNGAP1 variants for young children(<5 years old)have included global developmental delay and seizure/epilepsy.All of the children may present GDD before the age of two.The severity of developmental delay may be related to the type and location of the SYNGAP1 variants.