1例羊水质谱提示甲基丙二酸血症胎儿的产前诊断

Prenatal diagnosis of one fetus with methylmalonic acidemia indicated by amniotic fluid detected by mass spectrometry

目的探讨质谱技术(mass spectrometry,MS)应用于胎儿羊水检测遗传代谢病的临床价值。方法收集胎儿羊水上清液(为排除染色体异常行羊膜腔穿刺术所取、检测后剩余的),使用质谱检测羊水中代谢物水平,提取代谢物异常的胎儿羊水细胞DNA,行遗传代谢病的高通量基因检测,并一代测序验证。结果质谱提示胎儿羊水中丙酰肉碱(C3)为3.89μmol/L,C3/C2为0.53,甲基丙二酸为7.33mmol/mol肌酐,荧光免疫法提示同型半胱氨酸为21.8μmol/L,提示胎儿为MMA合并同型半胱氨酸血症患者。高通量测序和一代测序证实胎儿为MMACHC基因c.80A>G(p.Gln27Arg)和c.658_660delAAG(p.Lys220del)复合杂合变异导致的MMA合并同型半胱氨酸血症患儿,孕妇为MMACHC基因c.658_660delAAG(p.Lys220del)杂合变异携带者,配偶为MMACHC基因c.80A>G(p.Gln27Arg)杂合变异携带者。结论在不增加孕妇采样痛苦和不干扰其他检测流程的前提下,MS可推广于孕妇羊水且无MMA等遗传代谢病生育史的筛查,预防遗传代谢病胎儿出生。

Objective To evaluate the clinical value of mass spectrometry in detecting genetic metabolic diseases in fetal amniotic fluid.Methods The supernatant of fetal amniotic was collected by amniocentesis,from the pregnant women in order to eliminate fetal chromosomal abnormalities.The levels of metabolites in the amniotic fluid was detected by mass spectrometry.The DNA of fetal amniotic fluid cells with abnormal metabolites was extracted,and genetic metabolic disease was performed by high-throughput sequencing,and verified by Sanger sequencing.Results The Propionylcarnitine(C3)was 3.89 umol/L,C3/C2 was 0.53,Methylmalonic acid was 7.33 mmol/mol creatinine by tandem mass analysis and homocysteine was 21.8 umol/L by fluorescence immunoassay in fetal amniotic fluid.These results suggested that the fetus is Methylmalonic Acidemia cblC Type,who was affected by c.80A>G(p.Gln27Arg)and c.658_660delAAG(p.Lys220del)of MMACHC gene by High-throughput sequencing and Sanger sequencing.The pregnant woman was a heterozygous variant carrier of MMACHC gene c.658_660delAAG(p.Lys220del),and the spouse was a heterozygous variant carrier of MMACHC gene c.80A>G(p.Gln27Arg).Conclusion MS can be applied to screening the pregnant women amniotic fluid and no reproductive history of genetic metabolic diseases such as MMA,to prevent the birth of fetuses with genetic metabolic,neither increase the pain of pregnant women sampling,nor interfere with other testing procedures.