河南省瓜氨酸血症Ⅰ型的新生儿筛查及基因变异分析  

Newborn screening and gene variation analysis of citrullinemia type Ⅰ in Henan province

作　　者：朱昕赟 徐一卓 张洁[1] 李晓乐[1] 刘素娜[1] 倪敏[1] 任益慧 欧阳运佳 马坤 高彦博 马胜举 吕书博[1] 贾晨路[1] 赵德华[2] 石瑛[1] Zhu Xinyun;Xu Yizhuo;Zhang Jie;Li Xiaole;Liu Suna;Ni Min;Ren Yihui;Ouyang Yunjia;Ma Kun;Gao Yanbo;Ma Shengju;Lyu Shubo;Jia Chenlu;Zhao Dehua;Shi Ying(Department of Neonatal Screening,the Third Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China;Human Sperm Bank,the Third Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)

机构地区：[1]郑州大学第三附属医院新生儿疾病筛查科,郑州450052 [2]郑州大学第三附属医院人类精子库,郑州450052

出　　处：《中华实用儿科临床杂志》2024年第5期332-336,共5页Chinese Journal of Applied Clinical Pediatrics

基　　金：河南省医学科技攻关省部共建重点项目(SBGJ202102182);河南省科技厅攻关项目(212102310733);河南省医学科技攻关计划联合共建项目(LHGJ20200441,LHGJ20210443);河南省重点研发专项(231111312000)。

摘　　要：目的:总结河南人群瓜氨酸血症Ⅰ型的发病率及基因变异特点,为瓜氨酸血症Ⅰ型的早期诊断、治疗和遗传咨询提供依据。方法:横断面研究。回顾性分析2016年1月至2022年12月在郑州大学第三附属医院应用串联质谱法完成的河南省814625例新生儿的遗传代谢病筛查结果。采用二代高通量测序法对瓜氨酸血症Ⅰ型筛查阳性患儿进行ASS1基因变异分析及父母基因验证。对新检测到的ASS1基因变异使用罕见外显子组变体集成学习器(REVEL)方法分析表型-基因型相关性,并构建蛋白质三维结构模型进行生物信息学分析。结果:814625例新生儿中共确诊8例(1/101828)瓜氨酸血症Ⅰ型患儿。8例患儿均有特异性瓜氨酸水平增高。基因测序共检出12种变异,均为错义突变,其中包括5种新发现的变异:c.552C>A(p.N184K)、c.140C>T(p.A47V)、c.173A>G(p.K58R)、c.920G>A(p.R307H)和c.790G>A(p.G264S),其中c.552C>A检出率最高,占18.75%(3/16)。REVEL分析预测这5种变异均为有害性,ASS蛋白三维结构模型显示c.140C>T(p.A47V)和c.920G>A(p.R307H)未发生氨基酸残基间氢键数量的变化,而c.552C>A(p.N184K)、c.173A>G(p.K58R)和c.790G>A(p.G264S)导致氢键减少,可能会影响到ASS蛋白的功能。结论:河南省新生儿瓜氨酸血症Ⅰ型发病率为1/101828。新发现了5种变异,丰富了人类ASS1基因变异谱,为瓜氨酸血症Ⅰ型的早期诊断、治疗和遗传学研究提供了重要依据。Objective To summarize the incidence and gene variation characteristics of citrullinemia typeⅠin Henan population,and to provide evidence for early diagnosis,treatment and genetic counseling of citrullinemia typeⅠ.Methods A cross-sectional study.A total of 814625 neonates with inherited metabolic disorders screened by tandem mass spectrometry in the Third Affiliated Hospital of Zhengzhou University from January 2016 to December 2022 were retrospectively analyzed.ASS1 gene variation analysis and parental gene verification were performed in positive children with citrullinemia typeⅠby second-generation high-throughput sequencing.Rare exome variant ensemble learner(REVEL)method was used to analyze the phenotype-genotype correlation of novel ASS1 gene variations,and the three-dimensional structure model of proteins was constructed for bioinformatics analysis.Results A total of 8 cases(1/101828)of citrullinemia typeⅠwere diagnosed in 814625 neonates.All 8 cases showed increased levels of specific citrulline.A total of 12 ASS1 gene variants were detected by gene sequencing,all of which were missense mutations,including 5 novel variants:c.552C>A(p.N184K),c.140C>T(p.A47V),c.173A>G(p.K58R),c.920G>A(p.R307H),and c.790G>A(p.G264S),among which c.552C>A had the highest detection rate,accounting for 18.75%(3/16).REVEL analysis predicted that all the 5 novel variants were harmful.The three-dimensional structure model of the ASS protein showed that c.140C>T(p.A47V)and c.920G>A(p.R307H)did not change the number of hydrogen bonds between amino acid residues,while c.552C>A(p.N184K),c.173A>G(p.K58R)and c.790G>A(p.G264S)caused a decrease in hydrogen bonds,which might affect the function of the ASS protein.Conclusions The incidence of neonatal citrullinemia typeⅠin Henan province is 1/101828.Five novel variants are discovered,which enriches the variation spectrum of human ASS1 gene and provides an important basis for the early diagnosis,treatment and genetic research of citrullinemia typeⅠ.

关 键 词：新生儿筛查 瓜氨酸血症Ⅰ型 ASS1基因 变异分析 

分 类 号：R722.131[医药卫生—儿科]