MFN2基因错义变异致腓骨肌萎缩症2A2A型一个家系的遗传学分析  

Genetic analysis of a Chinese pedigree affected with Charcot-Marie-Tooth type 2A2A due to a missense variant of MFN2 gene

作　　者：韩玉 梁洁 吴杰斌 翟敬芳 Han Yu;Liang Jie;Wu Jiebin;Zhai Jingfang(Prenatal Diagnosis Center,Xuzhou Central Hospital,Xuzhou Clinical College of Xuzhou Medical University,Xuzhou,Jiangsu 221009,China)

机构地区：[1]徐州医科大学徐州临床学院、徐州市中心医院产前诊断中心,徐州221009

出　　处：《中华医学遗传学杂志》2025年第1期74-81,共8页Chinese Journal of Medical Genetics

基　　金：徐州医科大学创新团队项目(XZFC202305)。

摘　　要：目的探讨1个腓骨肌萎缩症2A2A型(CMT2A2A)家系基因型与表型的相关性,为该家系再次妊娠提供帮助。方法选取2024年1月至8月因"下肢肌肉萎缩伴运动障碍"就诊于徐州市中心医院产前诊断中心的1个CMT2A2A家系为研究对象。收集该家系相关临床资料,采集相关成员外周血与胎儿羊水/绒毛样本并提取基因组DNA,对相关成员进行全外显子组测序(WES),对检出的变异位点进行Sanger测序家系验证、致病性分析及生物信息学分析。本研究已通过徐州市中心医院医学伦理委员会的审查(批准号:XZXY-LK-20240111-0019)。结果①家系中均为女性发病(先证者及其母亲、第1胎女儿),呈现发病年龄越早、双下肢萎缩越严重的现象。②WES与Sanger测序结果显示先证者及其母亲、第1胎女儿、第3胎胎儿均携带MFN2基因c.314C>T(p.Thr105Met)杂合错义变异,先证者哥哥、现任丈夫、第4胎胎儿均为野生型。③根据美国医学遗传学与基因组学学会(ACMG)相关指南与临床基因组资源中心(ClinGen)相关建议,上述变异被评定为致病性(PP1_Strong+PM1+PS3+PS4_Moderate+PP3_Moderate+PM2_Supporting)。④PROVEAN与Mutation Taster软件对上述变异预测结果分别为"有害"与"致病性";Uniprot及Jalview软件预测上述变异位点编码氨基酸在多个物种间具有保守性;ChEBI软件预测上述变异可导致第105位氨基酸的极性发生改变。经遗传咨询,先证者第3胎选择终止妊娠,第4胎继续妊娠中。结论MFN2基因c.314C>T(p.Thr105Met)错义变异可能为上述CMT2A2A型家系的遗传学病因,该变异的检出为某再次妊娠提供了依据。ObjectiveTo explore the genotype-phenotype correlation in a Charcot-Marie-Tooth type 2A2A(CMT2A2A)pedigree and to provide genetic counseling for its subsequent pregnancies.MethodsA Chinese pedigree presenting with"lower limb muscle atrophy and movement disorders"at the Prenatal Diagnosis Center of Xuzhou Central Hospital between January and August 2024 was selected as the study subject.Relevant clinical data were collected from the pedigree members.Peripheral blood samples from affected individuals,and amniotic fluid and/or chorionic villus samples were obtained for DNA extraction.Whole exome sequencing(WES)was carried out.Candidate variants were verified by Sanger sequencing.Pathogenicity assessment and bioinformatic analysis were conducted.This study was approved by the Medical Ethics Committee of Xuzhou Central Hospital(Ethics No.XZXY-LK-20240111-0019).ResultsAll affected individuals in this pedigree were females,whom included the proband,her mother,and her first daughter.Earlier age of onset was associated with more severe lower limb atrophy.A heterozygous missense variant of the MFN2 gene,namely c.314C>T(p.Thr105Met),was identified in the proband,her mother,daughter,and the third fetus from a re-marriage.The same variant was absent in her elder brother,current husband,and her fourth fetus.Based on the guidelines from American College of Medical Genetics and Genomics(ACMG)and recommendations from Clinical Genome Resources(ClinGen),the variant was classified as pathogenic(PP1_Strong+PM1+PS3+PS4_Moderate+PP3_Moderate+PM2_Supporting).Analyses with PROVEAN and Mutation Taster had categorized the variant as"deleterious"and"disease-causing",respectively.Analysis with Uniprot and Jalview showed that the affected amino acid residue is conserved across multiple species.ChEBI software predicted that the variant may alter the polarity of the 105th amino acid residue.ConclusionThe c.314C>T(p.Thr105Met)missense variant of the MFN2 gene probably underlie the CMT2A2A in this pedigree.Above finding has enabled prenatal diagn

关 键 词：腓骨肌萎缩症2A2A型 MFN2基因 错义变异 全外显子组测序 

分 类 号：R714.5[医药卫生—妇产科学]