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Noninvasive prenatal diagnosis for Haemophilia A by a haplotype-based approach using cell-free fetal DNA in maternal plasma

By Chao Chen, Jun Sun, Yun Yang, Lu Jiang, Fengyu Guo, Yaping Zhu, Dan Li, Renhua Wu, Rong Lu, Mei Zhao, Fang Chen, Peixiang Ni, Zhihui He, Zhiyu Peng

Posted 28 Feb 2019
bioRxiv DOI: 10.1101/563429

Because of the background of maternal DNA and technical obstacles in determining the inversion breakpoint in plasma, the direct detection of intron 22 inversion in the F8 gene is impracticable. A haplotype-based method could potentially solve this problem by analyzing mutation-linked polymorphism sites. This study aimed to demonstrate the feasibility of haplotype-based noninvasive prenatal diagnosis for Haemophilia A. Two families affected by Haemophilia A participated in our study. Maternal haplotypes associated with pathogenic mutations were generated using targeted region genotypes of the mothers and the probands. Combined with the maternal pathogenic haplotypes, a hidden Markov Model was constructed to deduce fetal haplotypes using high-coverage targeted sequencing of maternal plasma DNA. The presence of a pathogenic haplotype in a male indicated an affected fetus, and that in a female indicated a carrier. Prenatal diagnoses were confirmed with amniocentesis and long-distance PCR. The haplotype-based noninvasive prenatal diagnosis of Haemophilia A was successfully performed. One fetus was identified to be Hemophilia A-negative and the other fetus was identified as a carrier; the results were confirmed by amniocentesis. Our research demonstrated the feasibility of noninvasive prenatal diagnosis of Hemophilia A caused by intron 22 inversion in the F8 gene using a haplotype-based approach.

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