四例异戊酸血症患儿的IVD基因变异分析  

Analysis of IVD gene variants in four children with isovalerate acidemia

作　　者：谭建强[1] 郑敏 蔡稔 曾婷 尹彪 杨金玲[1] 韦拔 畅荣妮 蒋永江 袁德健 潘莉珍 黄丽华[1] 宁海萍 韦江艳 陈大宇[1] Tan Jianqiang;Zheng Min;Cai Ren;Zeng Ting;Yin Biao;Yang Jinling;Wei Ba;Chang Ronni;Jiang Yongjiang;Yuan Dejian;Pan Lizhen;Huang Lihua;Ning Haiping;Wei Jiangyan;Chen Dayu(Liuzhou Institute of Reproduction and Genetics,Liuzhou Maternal and Child Health Care Hospital,the Affiliated Maternity Hospital and Affiliated Children′s Hospital of Guangxi University of Science and Technology,Liuzhou,Guangxi 545001,China;Guangzhou Women and Children Medical Center,Guangzhou,Guangdong 510623,China)

机构地区：[1]柳州市妇幼保健院,柳州市生殖与遗传研究所,广西科技大学附属妇产医院儿童医院,柳州545001 [2]广州市妇女儿童医疗中心,广州510623

出　　处：《中华医学遗传学杂志》2022年第12期1339-1343,共5页Chinese Journal of Medical Genetics

基　　金：柳州市科学研究与技术开发计划(2017BH20313、2018AF10501、2020NBAB0803)。

摘　　要：目的:对4例临床拟诊为异戊酸血症(isovaleric acidemia,IVA)的患儿进行IVD基因变异分析。方法:应用串联质谱技术对111986例新生儿以及7461例疑似遗传代谢病的住院患儿进行酰基肉碱筛查,对血异戊酰肉碱(C5)水平显著升高者进行尿有机酸分析及IVD基因变异检测。结果:共检出IVA患儿4例,包括2例经新生儿筛查发现的无症状患儿(0.018‰,2/111986)以及2例住院患儿(0.268‰,2/7461),后者表现为汗脚样气味、喂养困难、神志不清、嗜睡、昏迷、高血氨、高血糖、血细胞三系降低以及代谢性酸中毒等。4例患儿的酰基肉碱筛查提示C5、C5/乙酰基肉碱(C2)显著升高,尿有机酸分析提示尿异戊酰甘氨酸及3-羟基异戊酸升高。共检出8个IVD基因变异,共5种类型,分别为c.158G>A(p.Arg53His)、c.214G>A(p.Asp72Asn)、c.548C>T(p.Ala183Val)、c.757A>G(p.Thr253Ala)和c.1208A>G(p.Tyr403Cys),其中c.548C>T、c.757A>G既往未见报道。2095例正常新生儿的高通量测序未检出上述两种变异位点,根据美国医学遗传学与基因组学学会相关指南评级为可能致病。结论:本地区IVA的患病率偏高。对代谢异常的新生儿建议进行常规遗传代谢病筛查。上述发现丰富了IVD基因的变异谱。Objective To detect variants of IVD gene among 4 neonates with suspected isovalerate acidemia in order to provide a guidance for clinical treatment.Methods 111986 newborns and 7461 hospitalized children with suspected metabolic disorders were screened for acyl carnitine by tandem mass spectrometry.Those showing a significant increase in serum isovaleryl carnitine(C5)were analyzed for urinary organic acid and variants of the IVD gene.Results Four cases of isovalerate acidemia were detected,which included 2 asymptomatic newborns(0.018‰,2/111986)and 2 children suspected for metabolic genetic diseases(0.268‰,2/7461).The formers had no obvious clinical symptoms.Analysis of acyl carnitine has suggested a significant increase in C5,and urinary organic acid analysis has shown an increase in isovaleryl glycine and 3-hydroxyisovalerate.Laboratory tests of the two hospitalized children revealed high blood ammonia,hyperglycemia,decreased red blood cells,white blood cells,platelets and metabolic acidosis.The main clinical manifestations have included sweaty foot-like odor,feeding difficulty,confusion,drowsiness,and coma.Eight variants(5 types)were detected,which included c.158G>A(p.Arg53His),c.214G>A(p.Asp72Asn),c.548C>T(p.Ala183Val),c.757A>G(p.Thr253Ala)and 1208A>G(p.Tyr403Cys).Among these,c.548C>T and c.757A>G were unreported previously.None of the variants was detected by next generation sequencing of 2095 healthy newborns,and all variants were predicted to be likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics.Conclusion The incidence of isovalerate acidemia in Liuzhou area is quite high.Screening of metabolic genetic diseases is therefore recommended for newborns with abnormal metabolism.The discovery of novel variants has enriched the mutational spectrum of the IVD gene.

关 键 词：遗传代谢病 串联质谱 异戊酸血症 异戊酰辅酶A脱氢酶 IVD基因 

分 类 号：R725.8[医药卫生—儿科] R440[医药卫生—临床医学]