Abstract：Objective To study gene mutations in four pedigrees with methymalonic aciduria, as well as the feasibility of prenatal diagnosis of methymalonic aciduria. Methods High-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 amplification primers were designed for each locus, and PCR and direct sequencing were performed to validate the sequencing in the first 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. Results In 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.Conclusions Identification of gene mutations helps with prenatal diagnosis in pedigrees with methymalonic aciduria.
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