4个甲基丙二酸尿症的家系基因突变分析及其胎儿产前诊断

目的 分析4 个甲基丙二酸尿症（MMA）的家系基因突变情况，阐明开展MMA 基因突变分析及产前诊断的意义。方法 对诊断为MMA 的先证者或其父母行相关基因的高通量测序，确定基因突变位点，并采用聚合酶链反应和直接测序法对家系行一代测序验证。家系1、3、4 于先证者母亲再次妊娠11~13 周时超声引导下行绒毛活检，进行早期产前诊断。结果 家系1 先证者父亲检出MUT 基因c.656A > T 杂合突变，先证者母亲检出c.729-730insTT 杂合突变；早期产前诊断发现胎儿为c.656A > T 和c.729-730insTT 双重杂合突变，终止妊娠。家系2 先证者检出MUT 基因c.1106G > A 和c.755-756insA 双重杂合突变，c.1106G > A 来自父亲，c.755-756insA 来自母亲。家系3 先证者检出MMACHC 基因c.217C > T 和c.609G > A 双重杂合突变，c.217C > T 来自父亲，c.609G > A 来自母亲；产前诊断提示胎儿携带c.609G > A 杂合突变，胎儿出生时脐血检测结果与产前诊断一致。家系4 先证者检出MMACHC 基因c.609G > A 和c.567dupT 双重杂合突变，c.609G > A 来自父亲，c.567dupT 来自母亲；产前诊断提示胎儿携带c.567dupT 杂合突变，胎儿顺利出生，脐血检测结果与产前诊断一致。结论 明确基因突变有助于MMA 家系行产前诊断，避免缺陷患儿出生。

Gene mutation analysis and prenatal diagnosis of four pedigrees with methymalonic aciduria

ObjectiveTo study gene mutations in four pedigrees with methymalonic aciduria, as well as the feasibility of prenatal diagnosis of methymalonic aciduria.MethodsHigh-throughput sequencing was performed for related genes in the peripheral blood of children or parents who were diagnosed with methymalonic aciduria to identify the loci with mutations. Then ampliifcation primers were designed for each locus, and PCR and direct sequencing were performed to validate the sequencing in the ifrst generation in the four pedigrees. Whether the mutations were pathogenic were determined with reference to literature review and medical history. In the pedigrees 1, 3, and 4, ultrasound-guided chorionic villi biopsy was performed at weeks 11-13 of pregnancy to perform early prenatal diagnosis.ResultsIn pedigree 1, c.656A>T and c.729-730insTT heterozygous mutations in the MUT gene were detected in the proband’s father and mother, respectively. Early prenatal diagnosis showed c.656A>T and c.729-730insTT double heterozygous mutations in the fetus. The couple decided to terminate pregnancy. In pedigree 2, c.1106G>A and c.755-756insA double heterozygous mutations in the MUT gene were detected in the proband. c.1106G>A came from the father and c.755-756insA came from the mother. In pedigree 3, c.217C>T and c.609G>A double heterozygous mutations in the MMACHC gene were detected in the proband. c.217C>T came from the father and c.609G>A came from the mother. Prenatal diagnosis showed c.609G>A heterozygous mutation in the fetus. The baby was successfully delivered, and the result of umbilical cord blood testing was consistent with the prenatal diagnosis. In pedigree 4, c.609G>A and c.567dupT double heterozygous mutations in the MMACHC gene were detected in the proband. c.609G>A came from the father
and c.567dupT came from the mother. Prenatal diagnosis showed c.567dupT heterozygous mutation in the fetus. The baby was successfully delivered, and the result of umbilical cord blood testing was consistent with the prenatal diagnosis. ConclusionsIdentiifcation of gene mutations helps with prenatal diagnosis in pedigrees with methymalonic aciduria.