Clinical-grade whole genome sequencing-based haplarithmisis enables all forms of preimplantation genetic testing

High-throughput sequencing technologies have increasingly led to discovery of disease-causing genetic variants, primarily in postnatal multi-cell DNA samples. However, applying these technologies to preimplantation genetic testing (PGT) in nuclear or mitochondrial DNA from single or few-cells biopsied from in vitro fertilised (IVF) embryos is challenging. PGT aims to select IVF embryos without genetic abnormalities. Although genotyping-by-sequencing (GBS)-based haplotyping methods enabled PGT for monogenic disorders (PGT-M), structural rearrangements (PGT-SR), and aneuploidies (PGT-A), they are labour intensive, only partially cover the genome and are troublesome for difficult loci and consanguineous couples. Here, we devise a simple, scalable and universal whole genome sequencing haplarithmisis-based approach enabling all forms of PGT in a single assay. In a comparison to state-of-the-art GBS-based PGT for nuclear DNA, shallow sequencing-based PGT, and PCR-based PGT for mitochondrial DNA, our approach alleviates technical limitations by decreasing whole genome amplification artifacts by 68.4%, increasing breadth of coverage by at least 4-fold, and reducing wet-lab turn-around-time by ~2.5-fold. Importantly, this method enables trio-based PGT-A for aneuploidy origin, an approach we coin PGT-AO, detects translocation breakpoints, and nuclear and mitochondrial single nucleotide variants and indels in base-resolution.

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Publication Details

Journal
Nature Communications
Published
2024-09-02
DOI
https://doi.org/10.1038/s41467-024-51508-1
Citations
16
Primary Topic
Prenatal Screening and Diagnostics
Type
article
Field-Weighted Citation Impact
17.75

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Clinical-grade whole genome sequencing-based haplarithmisis enables all forms of preimplantation genetic testing

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Clinical-grade whole genome sequencing-based haplarithmisis enables all forms of preimplantation genetic testing

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article en
16 citations

Abstract

High-throughput sequencing technologies have increasingly led to discovery of disease-causing genetic variants, primarily in postnatal multi-cell DNA samples. However, applying these technologies to preimplantation genetic testing (PGT) in nuclear or mitochondrial DNA from single or few-cells biopsied from in vitro fertilised (IVF) embryos is challenging. PGT aims to select IVF embryos without genetic abnormalities. Although genotyping-by-sequencing (GBS)-based haplotyping methods enabled PGT for monogenic disorders (PGT-M), structural rearrangements (PGT-SR), and aneuploidies (PGT-A), they are labour intensive, only partially cover the genome and are troublesome for difficult loci and consanguineous couples. Here, we devise a simple, scalable and universal whole genome sequencing haplarithmisis-based approach enabling all forms of PGT in a single assay. In a comparison to state-of-the-art GBS-based PGT for nuclear DNA, shallow sequencing-based PGT, and PCR-based PGT for mitochondrial DNA, our approach alleviates technical limitations by decreasing whole genome amplification artifacts by 68.4%, increasing breadth of coverage by at least 4-fold, and reducing wet-lab turn-around-time by ~2.5-fold. Importantly, this method enables trio-based PGT-A for aneuploidy origin, an approach we coin PGT-AO, detects translocation breakpoints, and nuclear and mitochondrial single nucleotide variants and indels in base-resolution.

Nature CommunicationsVol. 15(1)
Radboud University Nijmegen (NL), Maastricht University Medical Centre (NL), Radboud University Medical Center (NL), Karolinska Institutet (SE), Maastricht University (NL), Department of Health (TW)
European Commission, Universiteit Maastricht, Maastricht Universitair Medisch Centrum, Radboud Universitair Medisch Centrum, European Society of Human Reproduction and Embryology, HORIZON EUROPE Framework Programme
Decent work and economic growth
Openalex Percentile: Top 1%
Prenatal Screening and Diagnostics
17.75
DOIOpen Access PDFOpenAlex
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