RRM2B基因复合杂合突变致线粒体DNA耗竭综合征2例家系临床特征及遗传学分析  

Clinical characteristics and family genetic analysis affected with two cases of mitochondrial DNA depletion syndrome caused by complex heterozygous mutation of RRM2B gene

作　　者：莫李媚 羊芳菲 赵丽 姚如恩[2] 吴鸿雁 谢丹 高燕 贺影忠[2] Mo Limei;Yang Fangfei;Zhao Li;Yao Ruen;Wu Hongyan;Xie Dan;Gao Yan;He Yingzhong(Department of Pediatric Intensive Care Unit,Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai Children’s Medical Center,Hainan Branch,Sanya 572000,China;Department of Neurology,Children’s Medical Center of Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China)

机构地区：[1]上海交通大学医学院附属上海儿童医学中心海南医院儿童重症医学科,三亚572000 [2]上海交通大学医学院附属上海儿童医学中心神经内科,上海200127

出　　处：《国际遗传学杂志》2024年第1期32-39,共8页International Journal of Genetics

摘　　要：目的探讨RRM2B基因突变致线粒体DNA耗竭综合征(mitochondrial DNA depletion syndrome,MDDS)的临床特征及遗传信息。方法对可疑患儿进行全外显子测序筛查潜在的基因变异,Sanger测序进行家系验证,同时采用ClinVar数据库和REVEL等软件预测核苷酸、氨基酸变异对蛋白功能的影响。通过文献检索,对已报道的RRM2B基因突变患者的遗传资料进行分析,并对RRM2B基因突变的类型和频率进行评估。结果患儿,女,6个月24天,临床上表现为发育倒退、肌张力低下、呼吸衰竭、腹泻等症状,实验室检查提示乳酸酸中毒、肌酶增高,测序结果显示患儿RRM2B基因存在c.125T>G(p.Phe42Cys)和c.175G>C(p.Ala59Pro)复合杂合突变,分别遗传自其母亲和父亲,患儿哥哥临床症状相同,也同样携带该基因复合杂合突变。文献数据库未见c.125T>G(p.Phe42Cys)位点变异的相关文献报道,2022年有1例报道c.175G>C(p.Ala59Pro)位点突变,根据美国医学遗传学与基因组学学会指南,判定为可能致病性变异。RRM2B基因突变目前报道共105例患者62种变异(包含本研究纳入的2例患者),外显子E6和E9是突变热点,突变类型以错义突变多见。结论RRM2B基因c.125T>G(p.Phe42Cys)和c.175G>C(p.Ala59Pro)杂合突变是导致MDDS的突变位点,本研究结果加强了对该类疾病的临床特征和遗传性病因认识,同时扩展了RRM2B基因变异谱。Objective The purpose of this research is to investigate the clinical features and genetic information associated with mitochondrial DNA depletion syndrome(MDDS)caused by RRM2B gene mutation.Methods Whole-exome sequencing was performed to screen for potential genetic variation in suspicious children and Sanger sequencing was performed for family verification.Meanwhile,ClinVar database and REVEL software were used to predict the effect of nucleotide and amino acid variation on protein function.The genetic data of patients with RRM2B gene mutations were analyzed by literature search and the types and frequencies of RRM2B gene mutations were evaluated.Results The baby girl was six months and twenty-four days old.The clinical symptoms were regressive growth,hypotonia,respiratory failure,diarrhea and so on.Laboratory examination suggested lactic acidosis and increased muscle enzymes.Sequencing revealed that the child has carried compound heterozygous missense variants of the RRM2B gene,namely c.125T>G(p.Phe42Cys)and c.175G>C(p.Ala59Pro),which were respectively inherited from her mother and father,and both were likely pathogenic variants.The mutations of c.125T>G(p.Phe42Cys)was newly discovered mutation.Her older brother had the same clinical features and mutation.Sixty-two mutations in RRM2B gene were reported in 105 patients(including two patients included in this study).Exon 6 and Exon 9 were hot spots mutation and missense mutations were common.Conclusion The c.125T>G(p.Phe42Cys)and c.175G>C(p.Ala59Pro)compound heterozygous mutations of RRM2B gene may be the pathogenic genes of MDDS.The results of this study has strengthened the understanding of the clinical features and genetic etiology of this disease and expanded the mutation spectrum of the RRM2B gene.

关 键 词：线粒体DNA耗竭综合征 基因 乳酸酸中毒 核糖核苷酸还原酶 

分 类 号：R725.9[医药卫生—儿科]