新生儿尿素循环障碍筛查结果和基因突变特征分析
Analysis of the screening results for neonatal urea cycle disorders and gene mutation characteristics
孟伟 1邵媛媛 2杨池菊 3陈西贵 3徐鹏 3周成3
作者信息
- 1. 邹城市人民医院医学检验科,山东邹城 273500
- 2. 济宁市第一人民医院产科,山东济宁 272000
- 3. 济宁市妇幼保健计划生育服务中心新生儿疾病筛查中心,山东济宁 272000
- 折叠
摘要
目的 了解山东省济宁市新生儿尿素循环障碍疾病的发病率、串联质谱(MS/MS)筛查结果和基因突变特征.方法 采集2014年7月至2023年12月出生并参加遗传代谢病筛查的789886名新生儿足跟血样,用MS/MS检测血氨基酸浓度筛查尿素循环障碍疾病,用核酸质谱、二代测序检测突变基因,用Sanger测序验证.结果 从789886名新生儿中,共检出尿素循环障碍患儿40例,总发病率约为0.51/万.共检出6种尿素循环障碍疾病,其中希特林蛋白缺乏症最常见(20/40,50.00％),发病率约0.25/万;其次为瓜氨酸血症Ⅰ型(10/40,25.00％),发病率约0.13/万;鸟氨酸氨甲酰转移酶缺乏症(4/40,10.00％),发病率约0.05/万;精氨酸血症(3/40,7.50％)、氨甲酰磷酸合成酶缺乏症(2/40,5.00％)、精氨酸琥珀酰尿症(1/40,2.50％)少见.希特林蛋白缺乏症、瓜氨酸血症Ⅰ型和精氨酸琥珀酰尿症的MS/MS筛查指标瓜氨酸(Cit)升高伴Cit/苯丙氨酸(Phe)比值升高,鸟氨酸氨甲酰转移酶缺乏症和氨甲酰磷酸合成酶缺乏症的MS/MS筛查指标Cit降低伴Cit/Phe降低,精氨酸血症MS/MS筛查指标精氨酸(Arg)升高伴Arg/鸟氨酸(Orn)和Arg/Phe比值升高.从40例尿素循环障碍患儿中共检出6个突变基因,SLC25A13基因以复合杂合突变为主(15/20,75.00％),常见的突变位点为 c.852_855del(p.M285Pfs*2)(17/39,43.59％),其次为 c.1177+1G＞A(/)(4/39,10.26％);ASS1 基因以复合杂合突变为主(9/10,90.00％),突变位点以 c.952G＞T(p.A318S)和 c.953C＞T(p.A318V)常见(3/19,15.79％);OTC基因以半合子突变为主(3/4,75.00％),ARG1基因以复合杂合突变为主(2/2,100.00％),CPS1基因以杂合突变为主(2/2,100.00％),ASL基因以复合杂合为主(1/1,100.00％).5例携带一个突变位点的尿素循环障碍患儿均出现MS/MS筛查主要指标均异常,部分病例辅助检测指标异常或在正常范围.结论 山东省济宁市尿素循环障碍发病率为0.51/万,疾病构成以希特林蛋白缺乏症和瓜氨酸血症Ⅰ型最常见,c.852_855del(p.M285Pfs*2).IVS16ins3kb(p.A584Vfs*2)和 c.1177+1G＞A(/)为 SLC25A13基因热点突变位点,c.952G＞T(p.A318S)和 c.953C＞T(p.A318V)为ASS1基因的热点突变位点.
Abstract
Objective To understand the incidence rate,tandem mass spectrometry(MS/MS)screening results and gene mutation characteristics of neonatal urea cycle disorders in Jining City,Shandong Province.Methods Blood samples from 789886 newborns born from July 2014 to December 2023 and screened for genetic and metabolic diseases were collected,and the blood amino acid concentration was detected by nucleic acid mass spectrum and second-generation sequencing,and verified by Sanger sequencing.Results Forty children with urea cycle disorder were screened out of 789886 newborns,with an incidence rate of 0.51/10000.Six urea cycle disorders were detected,of which Hitler protein deficiency was the most common(20/40,50.00％),followed by type Ⅰ(10/40,25.00％of citrullinemia),about 0.13/million;transferase deficiency(4/40,10.00％),aminyl phosphosynthetase deficiency(2/40,5.00％)and arginine succinuria(1/40,2.50％).MS/MS screening index citrullinine(Cit)increased Hetering protein deficiency,citrullinemia type Ⅰ and arginine succinyluria with increased Cit/phenylalanine(Phe)ratio,MS/MS screening index Cit decreased ornithine carbamidyltransferase deficiency and carbamyl phosphate synthase deficiency with decreased Cit/Phe,argininemia MS/MS screening index arginine(Arg)with increased Arg/Ornithine(Orn)and Arg/Phe ratios.A total of six mutated genes were detected from 40 children with urea cycle disor-der,SLC25A13 Gene is dominated by compound heterozygous mutations(15/20,75.00％).The common mutation site is c.852_855del(p.M285Pfs*2)(17/39,43.59％).Followed by c.1177+1G＞A(/)(4/39,10.26％).The ASS1 gene is dominated by compound heterozygous mutations(9/10,90.00％).Mutation sites are common in c.952G＞T(p.A318S)and c.953C＞T(p.A318V)(3/19,15.79％).OTC genes are dominated by hemizygous mutations(3/4,75.00％).The ARG1 gene is dominated by compound heterozygous mutations(2/2,100.00％).The CPS1 gene is dominated by heterozygous mutations(2/2,100.00％).The ASL genes were mainly compound heterozygous(1/1,100.00％).All 5 children with urea cycle disorder carrying one mu-tation site showed the abnormal main indicators of MS/MS screening,and in some cases,the auxiliary detection indicators were abnormal or in the normal range.Conclusion The incidence of urea cycle disorder in Jining City,Shandong Province is 0.51/10000,and the most common Hetering protein deficiency and citrullinaemia type Ⅰ,c.852_855del(p.M285Pfs*2),IVS16ins3kb(p.A584Vfs*2)and c.1177+1G＞A(/)are the SLC25A13 gene hot spot mutation site,c.952G＞T(p.A318S)and c.953C＞T(p.A318V)are the hot spot mutation site of ASS1 gene.
关键词
尿素循环障碍/新生儿疾病筛查/串联质谱/基因分析Key words
urea cycle disorders/neonatal disease screening/tandem mass spectrometry/gene analysis引用本文复制引用
基金项目
济宁市重点研发计划项目(2020YXNS049)
出版年
2024
NETL
NSTL
万方数据