PT  - JOURNAL ARTICLE
AU  - Lianshu Han
AU  - Chao Chen
AU  - Fengyu Guo
AU  - Jun Ye
AU  - Zhiyu Peng
AU  - Wenjuan Qiu
AU  - Yaoshen Wang
AU  - Wei Li
AU  - Huiwen Zhang
AU  - Lili Liang
AU  - Yu Wang
AU  - Huanhuan Wang
AU  - Xing Ji
AU  - Jun Sun
AU  - Xuefan Gu
TI  - Noninvasive prenatal test of methylmalonic academia cblC type through targeted sequencing of cell-free DNA in maternal plasma
AID  - 10.1101/425918
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 425918
4099  - http://biorxiv.org/content/early/2018/09/24/425918.short
4100  - http://biorxiv.org/content/early/2018/09/24/425918.full
AB  - Methylmalonic acidemia (MMA) cblC type is the most frequent inborn error of intracellular cobalamin metabolism which is caused by mutations of MMACHC gene. Non-invasive test of MMA for pregnant women facilitates safe and timely prenatal diagnosis of the disease. In our study, we aimed to design and validate a haplotype-based noninvasive prenatal test (NIPT) method for cblC type of MMA. Targeted capture sequencing using customized hybridization was performed utilizing gDNA (genomic DNA) of trios including parents and an affected proband to determine parental haplotypes associated with the mutant and wild allele. The fetal haplotype was inferred later based on the high depth sequencing data of maternal plasma as well as haplotype linkage analysis. The fetal genotypes deduced by NIPT were further validated by amniocentesis. Haplotype-based NIPT was successfully performed in 21 families. The results of NIPT of 21 families were all consistent with invasive prenatal diagnosis, which was interpreted in a blinded fashion. Three fetuses were identified as compound heterozygosity of MMACHC, 9 fetuses were carriers of MMACHC variant, and 9 fetuses were normal. These results indicated that the haplotype-based NIPT for MMA through small target capture region sequencing is technically accurate and feasible.