马凡综合征一家系临床研究和FBN1基因突变分析及产前诊断  

Pedigree analysis and prenatal diagnosis of FBN1 mutation for a family with Marfan syndrome

作　　者：康健捷 王显悦 莫桂玲 王晓武 马涛 林曦 张本 张卫达 杨红军 KANG Jianjie;WANG Xianyue;MO Guiling;WANG Xiaowu;MA Tao;LIN Xi;ZHANG Ben;ZHANG Weida;YANG Hongjun(Department of Neurology,General Hospital of Southern Theatre Command of PLA,Guangzhou 510010,China;Graduate School,Naval Medical University of PLA,Shanghai 200433,China;不详)

机构地区：[1]中国人民解放军南部战区总医院神经内科,广州510010 [2]中国人民解放军海军军医大学研究生院,上海200433 [3]中国人民解放军南部战区总医院心脏外科,广州510010 [4]广州金域检验中心有限公司,广州510010

出　　处：《实用医学杂志》2019年第24期3778-3782,共5页The Journal of Practical Medicine

基　　金：国家自然科学基金面上项目(编号：81671885);国家自然科学基金项目(编号：81500298);国家科技支撑计划(编号：2011BAI11B21);广州市科技计划项目(编号：201707010066);广州市珠江科技新星专项(编号：201610010094)

摘　　要：目的分析一马凡综合征(Marfan syndrome,MFS)家系的临床特征,进行原纤维蛋白-1基因(FBN1)突变分析,明确该家系的致病基因,以加强对此病的认识,提高早期诊断率,并对1例MFS孕妇进行产前诊断。方法描述一家系8例患者的临床表现,提取先证者及其家族成员外周血DNA,用PCR和DNA测序技术检测FBN1基因外显子中的潜在突变。提取MFS孕妇羊水细胞DNA和培养后羊水细胞的RNA,RT-PCR扩增RNA检测该家系所发现的阳性位点。结果该家系的遗传方式为常染色体显性遗传,4代共有8例患者,其中4例在47~59岁猝死,先证者和其他3例存活患者均具有心血管系统的异常(主动脉根部夹层或主动脉根部扩张)、晶状体脱位、高度近视及MFS的特征性骨骼改变,并随着年龄的增长而逐步加重。基因检测显示先证者FBN1基因54号外显子存在c.6554T>C(p.Ile2185Thr)错义突变,其他3例存活患者均发现该位点突变,而表型正常的成员未发现该突变。胎儿羊水细胞的DNA与羊水培养细胞RNA均发现该位点的突变。结论FBN1基因错义突变c.6554T>C(p.Ile2185Thr)为该家系致病的分子基础,基因检测有助于早期明确诊断以便尽早干预治疗,避免夹层动脉破裂导致猝死的不良结局。该MFS孕妇的胎儿遗传有该FBN1的致病突变,给双亲决定是否终止妊娠提供参考,有助于患病家族的优生优育。Objective To study the clinical phenotype and the mutation of fibrillin-1(FBN1)gene in a family with Marfan syndrome(MFS)and provide prenatal diagnosis for a pregnant woman with Marfan syndrome in the family.Methods The clinical manifestation of all patients in the MFS family were collected and analyzed.The genomic DNA was extracted from peripheral blood of the proband and his family members.Potential mutations in exons of FBN1 were detected with PCR.The genomic DNA of the fetus was obtained from amniotic fluid cells of the proband and RNA was from the cultured amniotic fluid cells.The RNA of amniotic fluid cells was amplified by RTPCR and the exon corresponding to FBN1 mutation was sequenced.Results The hereditary mode of this family was autosomal dominant,and there were 8 patients in the family among the 4 generations.Four of them died suddenly between the ages of 47 and 59.The probands and the other 3 survivors all had cardiovascular system abnormalities(aortic root dissection or aortic root dilation),lens dislocation,high myopia,and the characteristic bone changes of MFS,which gradually worsened with age.A missense mutation(c.6554 T>C,p.Ile2185 Thr)in exon 54 of FBN1 was detected in the proband.The four surviving patients carried the same genetic variation,however,no identical mutation was observed in the other members with normalphenotype in this family.The missense mutation at the locus was observed in the DNA and RNA of both amniotic fluid cells and cultured amniotic fluid cells.Conclusions Missense mutation of FBN1 gene c.6554 T>c(p.ile2185 thr)is the molecular basis of the disease in this family.Genetic testing is helpful for early diagnosis and early intervention to avoid the adverse outcomes of sudden death caused by rupture of dissecting artery.The fetus of this MFS pregnant woman has the pathogenic mutation of FBN1,which provides a reference for parents to decide whether to terminate the pregnancy and contributes to the eugenics of the affected family.

关 键 词：MARFAN综合征 原纤维蛋白-1 升主动脉扩张 基因突变 产前诊断 

分 类 号：R71[医药卫生—妇产科学]