Noninvasive prenatal diagnosis by genome-wide haplotyping of cell-free plasma DNA

Huiwen Che, Darine Villela, Eftychia Dimitriadou, Cindy Melotte, Nathalie Brison, Maria Neofytou, Kris Van den Bogaert, Olga Tsuiko, Koen Devriendt, Eric Legius, Masoud Zamani Esteki, Thierry Voet, Joris Robert Vermeesch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Purpose Whereas noninvasive prenatal screening for aneuploidies is widely implemented, there is an increasing need for universal approaches for noninvasive prenatal screening for monogenic diseases. Here, we present a cost-effective, generic cell-free fetal DNA (cffDNA) haplotyping approach to scan the fetal genome for the presence of inherited monogenic diseases. Methods Families participating in the preimplantation genetic testing for monogenic disorders (PGT-M) program were recruited for this study. Two hundred fifty thousand single-nucleotide polymorphisms (SNPs) captured from maternal plasma DNA along with genomic DNA from family members were massively parallel sequenced. Parental genotypes were phased via an available genotype from a close relative, and the fetal genome-wide haplotype and copy number were determined using cffDNA haplotyping analysis based on estimation and segmentation of fetal allele presence in the maternal plasma. Results In all families tested, mutational profiles from cffDNA haplotyping are consistent with embryo biopsy profiles. Genome-wide fetal haplotypes are on average 97% concordant with the newborn haplotypes and embryo haplotypes. Conclusion We demonstrate that genome-wide targeted capture and sequencing of polymorphic SNPs from maternal plasma cell-free DNA (cfDNA) allows haplotyping and copy-number profiling of the fetal genome during pregnancy. The method enables the accurate reconstruction of the fetal haplotypes and can be easily implemented in clinical practice.

Original languageEnglish
Pages (from-to)962-973
Number of pages12
JournalGenetics in Medicine
Issue number5
Publication statusPublished - May 2020


  • noninvasive prenatal testing
  • NIPD
  • cfDNA
  • genome-wide haplotyping
  • NIPS
  • COST
  • RISK


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