GENOME-WIDE PROFILING AND HAPLOTYPING OF CELL-FREE DNA ENABLING COMBINED NON-INVASIVE PRENATAL DIAGNOSIS OF INHERITED MONOGENIC DISEASES AND ANEUPLOIDY

Non-invasive prenatal diagnosis for the common trisomies 21, 18 and 13 has become standard of care in many countries world-wide. We developed methods that enable not only the detection of those common trisomies but leverage the identification of all fetal and maternal genomic and chromosomal disorders. As of July 2017 NIPT is reimbursed for all pregnant women in Belgium, so the outcome of this screening program will be presented, as well as our innovative NIPT pipeline. Non-invasive prenatal diagnosis (NIPD) for monogenic diseases has only been tested on a small number of genes using a locus-specific approach and has not become widely implemented. Here, we present a new method that enables the deduction of fetal haplotype to detect inherited monogenic diseases and aneuploidy. Using targeted sequencing in a genome-wide level of resolution, parental haplotype inheritance in the fetus was determined non-invasively with high accuracy based on cfDNA haplotyping analysis. In all clinical cases, the haplotypes blocks linked with the wild-type allele were correctly identified, and a maternally inherited trisomy case was properly deduced. The method is generic and can deduce the presence or absence of any inherited disease allele. Moreover, it leverage the genome wide fetal haplotype at relatively low cost. Since genome wide haplotyping of embryos (karyomapping or OnePGT) enables the reconstruction of genome-wide haplotypes, copy-number profiles and are able to determine the segregational origin of haplotypes, those methodologies are being implemented as a generic method for preimplantation genetic testing (PGT) in many IVF laboratories. This non-invasive prenatal haplotyping approach can also confirm that the fetus is derived from the embryo transferred and will replace invasive prenatal confirmation testing. Non-invasive prenatal diagnosis for the common trisomies 21, 18 and 13 has become standard of care in many countries world-wide. We developed methods that enable not only the detection of those common trisomies but leverage the identification of all fetal and maternal genomic and chromosomal disorders. As of July 2017 NIPT is reimbursed for all pregnant women in Belgium, so the outcome of this screening program will be presented, as well as our innovative NIPT pipeline. Non-invasive prenatal diagnosis (NIPD) for monogenic diseases has only been tested on a small number of genes using a locus-specific approach and has not become widely implemented. Here, we present a new method that enables the deduction of fetal haplotype to detect inherited monogenic diseases and aneuploidy. Using targeted sequencing in a genome-wide level of resolution, parental haplotype inheritance in the fetus was determined non-invasively with high accuracy based on cfDNA haplotyping analysis. In all clinical cases, the haplotypes blocks linked with the wild-type allele were correctly identified, and a maternally inherited trisomy case was properly deduced. The method is generic and can deduce the presence or absence of any inherited disease allele. Moreover, it leverage the genome wide fetal haplotype at relatively low cost. Since genome wide haplotyping of embryos (karyomapping or OnePGT) enables the reconstruction of genome-wide haplotypes, copy-number profiles and are able to determine the segregational origin of haplotypes, those methodologies are being implemented as a generic method for preimplantation genetic testing (PGT) in many IVF laboratories. This non-invasive prenatal haplotyping approach can also confirm that the fetus is derived from the embryo transferred and will replace invasive prenatal confirmation testing.