迟发型鸟氨酸氨甲酰转移酶缺乏症患儿4例的OTC基因变异分析  

Analysis of OTC gene variants in four children with delayed onset orinithine transcarbamylase deficiency

作　　者：谢垒[1] 王瑶 马威[1] 范晓蕾[1] 庞璐璐 魏二虎[1] 王怀立[1] Xie Lei;Wang Yao;Ma Wei;Fan Xiaolei;Pang Lulu;Wei Erhu;Wang Huaili(Pediatric Intensive Care Unit,the First Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450052,China)

机构地区：[1]郑州大学第一附属医院儿童重症监护室,郑州450052

出　　处：《中华医学遗传学杂志》2023年第3期328-331,共4页Chinese Journal of Medical Genetics

摘　　要：目的对4例迟发型鸟氨酸氨甲酰转移酶缺乏症(OTCD)患儿的临床特点及OTC基因变异进行分析。方法收集2020年1月至2021年4月收治于郑州大学第一附属医院儿童重症监护室的4例OTCD患儿的临床资料,抽取患儿及父母的外周血样,用高通量测序的方法进行全外显子组测序(WES),对候选致病变异进行Sanger测序验证及生物信息学分析变异蛋白结构。结果4例患儿的临床表现主要包括呕吐、抽搐和意识障碍。WES结果显示患儿1的OTC基因第5外显子存在c.421C>T(p.R141X)变异。患儿2和3的OTC基因第2外显子均存在c.119G>A(p.R40H)变异。患儿4的OTC基因第5外显子存在c.607T>A(p.S203T)变异。c.607T>A变异既往未见报道,根据美国医学遗传学与基因组学学会变异相关指南,判定为可能致病性变异(PM1+PM2_Supporting+PP3+PP4),蛋白结构预测显示该变异将造成氢键断裂。Sanger测序验证患儿2~4的变异均为母源性。结论OTC基因变异可能是4例迟发型OTCD患儿的遗传学病因。c.607T>A的发现丰富了OTC基因的变异谱。Objective To analyze the clinical manifestation and genetic basis for four children with delayed onset ornithine transcarbamylase deficiency(OTCD).Methods Clinical data of 4 children with OTCD admitted to the Pediatric Intensive Care Unit of the First Affiliated Hospital of Zhengzhou University from January 2020 to April 2021 were reviewed.Peripheral blood samples of the patients and their parents were collected and subjected to whole exome sequencing(WES).Bioinformatic analysis and Sanger sequencing verification were carried out to verify the candidate variants.Impact of the candidate variants on the protein structure was also predicted.Results The clinical manifestations of the 4 children included vomiting,convulsion and disturbance of consciousness.WES revealed that the child 1 was heterozygous for a c.421C>T(p.R141X)variant in exon 5,children 2 and 3 were hemizygous for a c.119G>A(p.R40H)variant in exon 2,and child 4 was hemizygous for a c.607T>A(p.S203T)variant in exon 5 of the OTC gene.Among these,the c.607T>A variant was unreported previously and predicted to be pathogenic(PM1+PM2_Supporting+PP3+PP4).Bioinformatic analysis has predicted that the variant may result in breakage of hydrogen bonds and alter the protein structure and function.Sanger sequencing confirmed that the variants in children 2 to 4 have derived from their mothers.Conclusion The pathogenic variants of the OTC gene probably underlay the delayed OTCD in 4 children.The discovery of the c.607T>A variant has enriched the mutational spectrum of the OTC gene.

关 键 词：鸟氨酸氨甲酰转移酶缺乏症 高氨血症 血尿有机酸检测 OTC基因 

分 类 号：R725.9[医药卫生—儿科]