Noninvasive prenatal testing for autosomal recessive conditions by maternal plasma sequencing in a case of congenital deafness.
OBJECTIVE
The goals of our study were to develop a noninvasive prenatal test for autosomal recessive monogenic conditions and to prove its overall feasibility and potential for clinical integration.


METHODS
We recruited a pregnant woman and her spouse, who had a proband child suffering from congenital deafness, and obtained the target-region sequencing data from a semicustom array that used genomic and maternal plasma DNA from three generations of this family. A haplotype-assisted strategy was developed to detect whether the fetus inherited the pathogenic mutations in the causative gene, GJB2. The parental haplotype was constructed using a trio strategy through two different processes, namely, the grandparent-assisted haplotype phasing process and the proband-assisted haplotype phasing process. The fetal haplotype was deduced afterward based on both the maternal plasma sequencing data and the parental haplotype.


RESULTS
The accuracy levels of paternal and maternal haplotypes obtained by grandparent-assisted haplotype phasing were 99.01 and 97.36%, respectively, and the proband-assisted haplotype phasing process yielded slightly lower accuracies of 98.73 and 96.79%, respectively. Fetal inheritance of the pathogenic gene was deduced correctly in both processes.


CONCLUSIONS
Our study indicates that the strategy of haplotype-based noninvasive prenatal testing for monogenic conditions has potential applications in clinical practice.
Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Meng
M
Meng
BGI-Shenzhen, Shenzhen, China.
Xuchao
X
Li
BGI-Shenzhen, Shenzhen, China.
Huijuan
H
Ge
1] BGI-Shenzhen, Shenzhen, China [2] Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Fang
F
Chen
Chinese PLA General Hospital, Beijing, China.
Mingyu
M
Han
BGI-Shenzhen, Shenzhen, China.
Yanyan
Y
Zhang
Chinese PLA General Hospital, Beijing, China.
Dongyang
D
Kang
BGI-Shenzhen, Shenzhen, China.
Weiwei
W
Xie
Chinese PLA General Hospital, Beijing, China.
Zhiying
Z
Gao
BGI-Shenzhen, Shenzhen, China.
Xiaoyu
X
Pan
Chinese PLA General Hospital, Beijing, China.
Pu
P
Dai
Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China.
Fanglu
F
Chi
BGI-Shenzhen, Shenzhen, China.
Shengpei
S
Chen
BGI-Shenzhen, Shenzhen, China.
Ping
P
Liu
BGI-Shenzhen, Shenzhen, China.
Chunlei
C
Zhang
1] BGI-Shenzhen, Shenzhen, China [2] BGI-Shanghai, BGI-Shenzhen, Shenzhen, China.
Jianjun
J
Cao
1] BGI-Shenzhen, Shenzhen, China [2] Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Hui
H
Jiang
1] BGI-Shenzhen, Shenzhen, China [2] Shenzhen Birth Defect Screening Project Lab, BGI-Shenzhen, Shenzhen, China.
Xun
X
Xu
1] BGI-Shenzhen, Shenzhen, China [2] Clinical Laboratory of BGI Health, Shenzhen, China.
Wei
W
Wang
Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
Tao
T
Duan
D000465:Algorithms; D000483:Alleles; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics; D003638:Deafness / Q000097:blood* / Q000151:congenital* / Q000235:genetics*; D005260:Female; D015723:Gene Library; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D008297:Male; D008390:Markov Chains; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA
D017630:Connexins; C000607042:GJB2 protein, human; D000072259:Connexin 26