Noninvasive prenatal diagnosis of hemophilia A by a haplotype-based approach using cell-free fetal DNA

Abstract

Aim: We aimed to demonstrate noninvasive prenatal diagnosis (NIPD) of hemophilia A (HA) using a haplotype-based approach. Methods: Two families at risk for HA were recruited for this study. First, maternal haplotypes associated with pathogenic variants were constructed using the genotypes of the mothers and probands. Then, fetal haplotypes were deduced using a maternal haplotype-assisted hidden Markov model. Finally, the NIPD results were further confirmed by invasive prenatal diagnosis. Results: Two fetal genotypes were successfully inferred, with one normal fetus and one carrier fetus. The NIPD results were confirmed by invasive prenatal diagnosis, with a 100% consistency rate. Conclusion: Our test has been shown to be accurate and reliable. With further validation in a large patient cohort, this haplotype-based approach could be feasible for the NIPD of HA and other X-linked single-gene disorders.

SUMMARY POINTS

We propose a haplotype-based noninvasive prenatal diagnosis approach for hemophilia A using a small target region. The genomic DNA of the parents and proband and cell-free DNA of maternal plasma are analyzed by targeted sequencing and maternal pathogenic haplotypes deduced using the genotypes of mother and proband. Then, fetal haplotypes were inferred using a hidden Markov model and Viterbi algorithm.