摘要
目的:分析甲基丙二酸血症合并同型半胱氨酸血症患儿基因突变类型及突变频率,探讨基因型与表型之间的关系。方法:采用液相串联质谱-非衍生法对石家庄市2014年1月—2018年3月出生的113810例新生儿进行酰基肉碱谱筛查,联合气相色谱-质谱及维生素B12负荷试验对可疑患儿进行确诊并分型,采用二代测序技术进行MMACHC、HCFC1基因突变分析,Sanger测序技术进行验证。结果:确诊的25例甲基丙二酸血症患儿中11例做了基因检测,3例为单纯型,8例为合并型。基因分析发现11种基因突变位点,已见报道8种,分别为C.666C>A、C.482G>A、C.656_658delAGA、c.609G>A、C.80A>G、C.394C>T、C.440_441del和C.599G>A;未见报道3种,分别为C.239A>G、C.4535A>T和C.4442C>T。突变频率分析表明C.482G>A较为常见,突变频率为0.25。随访发现8例合并型的患儿1例夭折,基因型为C.656_658delAGA/C.440_441del;3例发育迟缓,基因型分别为C.599G>A/C.656_658delAGA/C.4535A>T、C.609G>A/C.609G>A和C.80A>G/C.394C>T;其余4例无异常表现。结论:8例合并型甲基丙二酸血症患儿基因突变分析发现,C.482G>A为热点突变。基因型与临床症状及预后结合分析表明C.656_658delAGA/C.440_441del基因型致病性较强;基因型C.599G>A/C.656_658delAGA/C.4535A>T和C.80A>G/C.394C>T预后较差;基因突变位点C.656_658delAGA致病性较强,且预后差;基因突变位点C.482G>A预后相对较好。通过新生儿串联质谱筛查可及早发现甲基丙二酸血症患儿,明确患儿基因突变情况,可为家庭再生育指导、产前诊断及预后提供依据。
Objective:To analyze the mutation type and mutation frequency of methylmalonic acidemia and homocystinemia in children, and to explore the relationship between genotype and phenotype. Methods: A total of 113 810 newborns in Shijiazhuang city were screened for acylcarnitine spectrum by tandem mass spectrometry, and analyzed by gas chromatography-mass spectrometry (GC-MS) and vitamin B12 absorption test. The MMACHC and HCCFC1 gene mutations were analyzed using second -generation sequencing technology, and further characterized using Sanger sequencing. Results: 25 newborns with methylmalonic acidemia were diagnosed, of which 11 cases were genetically tested, 3 cases were of MMA simple type and 8 cases combined type. A total of 11 gene mutation sites were detected, of which 8 mutation sites have been reported: C.666C>A, C.482G>A, C. 656_658delAGA, c.609G>A, C.80A>G, C.394C>T, C.440_441del and C.599G>A. 3 novel mutations sites were identified: C.239A>G, C.4535A>T and C.4442C>T. The mutation frequency analysis showed that C. 482G>A was more common, and mutation frequency was 0.25. The follow -up visit showed that 1 case of 8 patients died, the genotype was C.656_658delAGA/C.440_441del, and that 3 cases stunted, the genotypes were C. 599G>A/C.656_658delAGA/C.4535A>T, C.609G>A/C.609G>A,C.80A>G/C. 394C>T. The remaining cases showed no abnormalities. Conclusions: The mutations of MMACHC and HCFC1 were analyzed in 8 cases with combined MMA, and C.482G>A was more common. Combined with clinical symptoms and prognosis, the C. 656_658delAGA /C.440_441del genotype is more pathogenic, the C.599G>A/C.656_658delAGA/C.4535A>T and C.80A>G/C.394C>T have poor prognosis. The gene mutation site C.656_658delAGA is highly pathogenic and poor prognosis. The prognosis of the mutation site C. 482G >A is relatively better. Neonatal tandem mass spectrometry screening can detect children with methylmalonic acidemia early, and the identification of gene mutations can provide evidence for family reproductive guidance, prenatal diagnosis and prognosis.
作者
贾立云
封纪珍
王熙
马翠霞
封露露
JIA Li-yun;FENG Ji-zhen;WANG Xi;MA Cui-xia;FENG Lu-lu(Department of Genetics, Shijiazhuang Maternaland Child Health Hospital, Shijiazhuang 050000, China)
出处
《国际生殖健康／计划生育杂志》
CAS
2019年第5期362-366,共5页
Journal of International Reproductive Health/Family Planning
基金
河北省医学科学研究重点课题(20191423)
关键词
新生儿筛查
甲基丙二酸
代谢缺陷
先天性
基因
突变
Neonatal screening
Methylmalonic acid
Metabolism,inborn errors
Genes
Mutation
