摘要目的：利用Sanger测序对45例甲基丙二酸血症结合同型半胱氨酸血症家系MMACHC基因的突变进行分析，并探讨其对甲基丙二酸血症结合同型半胱氨酸血症生育史家系再次生育前行产前诊断的可能性。方法采集2012至2015年来自郑州大学第一附属医院遗传咨询门诊的45例结合型甲基丙二酸血症先证者和先证者父母的外周血2 ml，提取基因组DNA，采用PCR产物直接测序法对MMACHC基因进行突变分析，明确每个家系的基因突变情况，并对再次怀孕的12对夫妇抽取胎儿绒毛进行产前诊断。结果45例家系共检测出14种MMACHC基因突变，最常见的突变为c．609G＞A（W203X），c．658－660delAAG（K220del）和c．80A＞G （Q27A）。其中2种为新突变，包括1个剪接位点突变（c．81＋1G＞A）和1个错义突变（c．665A＞G，p．Y222C）。突变频率最高的外显子为第4外显子。行产前诊断的12例家系中2例胎儿确定为 MMACHC 基因正常，7例胎儿为MMACHC基因杂合突变携带者，3例胎儿为 MMACHC 基因复合杂合突变或纯合突变患者。MMACHC基因正常或杂合突变携带者胎儿的家系选择继续妊娠，而MMACHC纯合突变或复合杂合突变患者胎儿的家系均选择终止妊娠，胎儿娩出后随访与产前诊断结果一致。结论本研究发现2个MMACHC基因新突变，证实对有结合型甲基丙二酸血症生育史的家系再次怀孕时进行产前MMACHC基因分析，可以避免生育甲基丙二酸血症患者。（中华检验医学杂志，2016，39：613－617）

abstractsObjective To analyse MMACHC mutations for 45 pedigrees with combined methylmalonic aciduria and homocyctinuria by Sanger sequencing, and to discuss the utility of prenatal genetic diagnosis for these pedigrees.Method Peripheral blood was collected from 45 probands and their parents from 2012-2015 in Genetic Counselling Clinic of the First Affiliated Hospital of Zhengzhou University, and the DNA were extracted from the blood.Then the coding sequence of MMACHC gene was amplified by PCR, and the PCR products were further sequenced to detect mutations for each pedigree.For 12 families, chorionic villus sampling was performed on the pregnant women to make prenatal genetic diagnosis.Result There were 14 distinct mutations detected in the 45 pedigrees, and the most frequent mutations are c.609G>A(W203X),c.658-660delAAG(K220del)and c.80A>G (Q27A).Two of those mutations have not been reported before:one is a splicing site mutation c.81+1G>A;while the other is a missense mutation c.665A>G,p.Y222C.Most mutations were found in exon 4.Among the 12 pedigrees who received prenatal diagnosis, 2 fetuses were normal, 7 fetuses were carriers of heterozygous mutation, and the other 3 fetuses were patients with compound heterozygous mutation or homozygous mutation.The couples whose fetuses were normal or carriers continued the gestation, while the couples whose fetuses were patients decided to terminate the pregnancy.After delivery, the outcome of the fetuses was the same as the prenatal diagnose results.Conclusion Two novel mutations of MMACHC were identified and prenatal genetic diagnosis helps to avoid the delivery of combined methylmalonic aciduria and homocyctinuria patients.