单纯型甲基丙二酸血症家系MUT基因变异的分析及产前诊断

Analysis of MUT gene mutations and prenatal diagnosis for 20 pedigrees affected with isolated methylmalonic aciduria

目的对20个单纯型甲基丙二酸血症家系MUT基因的变异进行测序分析，为家系产前诊断提供依据。方法应用PCR产物直接测序法对20例单纯型甲基丙二酸血症患儿及其父母的MUT基因进行变异检测和分析，明确基因变异情况，并对9名孕妇进行产前诊断。结果20例患儿的家系共检测出19种MUT基因变异，最常见的变异为C.323G〉A（P．Arg108His）、c．1106G〉A（P．Arg369His）、C．729_730insTT（P．D244Lfs＊39）和c．1107dupT（P．T370Yfs＊22）。C．920_923delTCTT（P．F307SIs＊6）、C．419T〉C（P．Leu140Pro）和C．613G〉A（P．Glu205Lys）为未报道过的新变异。Polyphen2和Mutationtaster软件预测这3个变异均可能致病。产前诊断结果显示1例胎儿未检测到MUT基因变异，3例胎儿为MUT基因杂合变异携带者，5例胎儿为MUT基因复合杂合变异或纯合变异患儿。MUT基因正常或杂合变异携带者胎儿的家系选择继续妊娠，而MUT基因纯合变异或复合杂合变异胎儿的家系均选择终止妊娠，胎儿娩出后随访结果与产前诊断结果一致。结论MUT基因突变分析结果为家系的产前诊断提供了依据，新变异的检出丰富了MUT基因突变谱。

Objective To analyze MUT gene variants among 20 pedigrees affected with isolated methylmalonic aciduria by Sanger sequencing. Methods Peripheral blood samples were collected from the 20 probands and their parents. Following DNA extraction, the coding regions of the MUT gene were subjected to PCR amplification and Sanger sequencing. For 9 pedigrees, chorionic villus sampling was performed for prenatal genetic diagnosis. Results Nineteen variants were detected in the 20 pedigrees, with the most common ones including c. 323G〉A （p. Argl08His）, c. 1106G〉A （p. Arg369His）, c. 729_730insTT（p. D244Lfs＊39）, and c. 1107dupT （p. T370Yfs ＊22）. Three variants were not reported previously, which included a small-scale deletion c. 920_923delTCTT （p. F307Sfs＊6） and two missense mutations c. 419T〉C （p. Leu140Pro） and 613G〉A （p. Glu205Lys）. For 9 pedigrees undergoing prenatal diagnosis, 1 fetus was normal, three were found to carry heterozygous mutations, while the remaining 5 fetuses have carried compound heterozygous mutations or homozygous mutations. Conclusion Three novel variants of the MUT gene have been identified.