Zong Yanan, Liu Ning, Zhao Zhenhua, Kong Xiangdong
Center of Prenatal Diagnosis, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
BMC Med Genet. 2015 Jul 7;16:48. doi: 10.1186/s12881-015-0196-8.
Combined methylmalonic aciduria and homocystinuria, cobalamin(cbl)C deficiency, is a rare disorder of intracellular vitamin B12(cbl) metabolism caused by mutations in the MMACHC gene. Both genetic and biochemical approach have been established to diagnose children and fetuses with cblC deficiency, while in China there is no report of prenatal genetic diagnosis of cblC deficiency. The aim of the present study was to characterize the mutational spectrum of cblC deficiency and investigate the feasibility of genetic-sequencing-based prenatal diagnosis for cblC deficiency.
10 pedigrees were recruited in this study with the probands clinically and biochemically confirmed combined methymalonic aciduria and homocystinuria. Peripheral blood samples were collected for MMACHC genetic test from the probands and their parents (4 probands had already dead) and 50 control subjects. The entire coding region and adjacent splice sites of MMACHC were sequenced. After the genotypes of the pedigrees were identified, chorionic villi sampling were performed for 3 high-risk pregnant women for prenatal genetic diagnosis.
A total of 7 mutations were identified: c.217C > T (R73X), c.394C > T (R132X), c.463G > C (G155R), c.609G > A (W203X), c.616C > T (R206W), c.658-660delAAG (220delK), and c.567dupT (I190YfsX13), as well as 2 polymophsims: c.321G > A(V107V), c.-302G > T. And G155R is a novel mutation that haven't been reported in the literatures. All the 6 probands identified with compound heterozygous mutations or homozygous mutations of MMACHC gene, and all the parents of the probands were found to have one MMACHC mutation at a heterozygous level. Prenatal diagnosis of fetuses from 3 families with a child affected cblC deficiency showed that one fetus had the same compound heterozygous mutations as the proband, one did not have MMACHC mutation, and the third fetus had a mutation at a heterozygous level of MMACHC gene. Results from the follow-ups were consistent with the prenatal diagnosis.
A novel mutation p.G155R of the MMACHC gene is identified. Genetic diagonsis is an accurate and convenient method for prenatal diagnosis and early intervention of combined methylmalonic aciduria and homocystinuria.
甲基丙二酸血症合并同型胱氨酸尿症，即钴胺素（cbl）C 缺乏症，是一种由 MMACHC 基因突变引起的细胞内维生素 B12（cbl）代谢罕见疾病。目前已建立了遗传和生化方法来诊断患有 cblC 缺乏症的儿童和胎儿，而在中国尚无 cblC 缺乏症产前基因诊断的报道。本研究的目的是确定 cblC 缺乏症的突变谱，并探讨基于基因测序的 cblC 缺乏症产前诊断的可行性。
本研究招募了 10 个家系，先证者经临床和生化确诊为甲基丙二酸血症合并同型胱氨酸尿症。采集先证者及其父母（4 名先证者已死亡）和 50 名对照者的外周血样本进行 MMACHC 基因检测。对 MMACHC 的整个编码区和相邻剪接位点进行测序。在确定家系的基因型后，对 3 名高危孕妇进行绒毛取样以进行产前基因诊断。
共鉴定出 7 种突变：c.217C＞T（R73X）、c.394C＞T（R132X）、c.463G＞C（G155R）、c.609G＞A（W203X）、c.616C＞T（R206W）、c.658 - 660delAAG（220delK）和 c.567dupT（I190YfsX13），以及 2 种多态性：c.321G＞A（V107V）、c.-302G＞T。G155R 是一种文献中尚未报道的新突变。所有 6 名先证者均鉴定出 MMACHC 基因的复合杂合突变或纯合突变，且先证者的所有父母均被发现有一个杂合水平的 MMACHC 突变。对 3 个有 cblC 缺乏症患儿家庭的胎儿进行产前诊断，结果显示一个胎儿具有与先证者相同的复合杂合突变，一个胎儿没有 MMACHC 突变，第三个胎儿在 MMACHC 基因杂合水平有一个突变。随访结果与产前诊断一致。
鉴定出 MMACHC 基因的一个新突变 p.G155R。基因诊断是甲基丙二酸血症合并同型胱氨酸尿症产前诊断和早期干预的准确、便捷方法。
