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Sci Rep. 2017 Aug 7;7(1):7427. doi: 10.1038/s41598-017-06828-2.

Noninvasive prenatal diagnosis of 21-Hydroxylase deficiency using target capture sequencing of maternal plasma DNA.

Ma D1, Yuan Y2,3,4, Luo C1, Wang Y2,3,4, Jiang T1, Guo F2,3,4, Zhang J1, Chen C2,3,4, Sun Y1, Cheng J1, Hu P1, Wang J4,5, Yang H4,5, Yi X4, Wang W2,3,4, Asan6,7,8, Xu Z9.

Author information

1
State key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China.
2
Binhai Genomics Institute, BGI-Tianjin, Tianjin, China.
3
Tianjin Translational Genomics Centre, BGI-Tianjin, Tianjin, China.
4
BGI-Shenzhen, Shenzhen, China.
5
James D. Watson Institute of Genome Sciences, Hangzhou, China.
6
Binhai Genomics Institute, BGI-Tianjin, Tianjin, China. asan@genomics.cn.
7
Tianjin Translational Genomics Centre, BGI-Tianjin, Tianjin, China. asan@genomics.cn.
8
BGI-Shenzhen, Shenzhen, China. asan@genomics.cn.
9
State key Laboratory of Reproductive Medicine, Department of Prenatal Diagnosis, Nanjing Maternity and Child Health Care Hospital, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, China. njxzf@126.com.

Abstract

Here, we aimed to validate a noninvasive method using capture sequencing for prenatal diagnosis of congenital adrenal hyperplasia due to 21-Hydroxylase deficiency (21-OHD). Noninvasive prenatal diagnosis (NIPD) of 21-OHD was based on 14 plasma samples collected from 12 families, including four plasma sample collected during the first trimester. Targeted capture sequencing was performed using genomic DNA from the parents and child trios to determine the pathogenic and wild-type alleles associated with the haplotypes. Maternal plasma DNA was also sequenced to determine the fetal inheritance of the allele using hidden Markov model-based haplotype linkage analysis. The effect of fetal DNA fraction and sequencing depth on the accuracy of NIPD was investigated. The lower limit of fetal DNA fraction was 2% and the threshold mean sequence depth was 38, suggesting potential advantage if used in early gestation. The CYP21A2 genotype of the fetus was accurately determined in all the 14 plasma samples as early as day 1 and 8 weeks of gestation. Results suggest the accuracy and feasibility of NIPD of 21-OHD using a small target capture region with a low threshold for fetal DNA fraction and sequence depth. Our method is cost-effective and suggests diagnostic applications in clinical practice.

PMID:
28785026
PMCID:
PMC5547133
DOI:
10.1038/s41598-017-06828-2
[Indexed for MEDLINE]
Free PMC Article

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