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

Anouk E. J. Janssen, Rebekka M. Koeck, Rick Essers, Ping Cao, Wanwisa Dijk, Marion Drüsedau, Jeroen Meekels, Burcu Yaldiz, Maartje Vorst, Bart Koning, Debby M. E. I. Hellebrekers, Servi J. C. Stevens, Su Ming Sun, Malou Heijligers, Sonja A. Munnik, Chris M. J. Uum, Jelle Achten, Lars Hamers, Marjan Naghdi, Lisenka E. L. M. Vissers, Ron J. T. Golde, Guido Wert, Jos C. F. M. Dreesen, Christine Die-Smulders, Edith Coonen, Han G. Brunner, Arthur Wijngaard, Aimee D. C. Paulussen and Masoud Zamani Esteki ()
Additional contact information
Anouk E. J. Janssen: Maastricht University Medical Centre (MUMC+)
Rebekka M. Koeck: Maastricht University Medical Centre (MUMC+)
Rick Essers: Maastricht University Medical Centre (MUMC+)
Ping Cao: Maastricht University Medical Centre (MUMC+)
Wanwisa Dijk: Maastricht University Medical Centre (MUMC+)
Marion Drüsedau: Maastricht University Medical Centre (MUMC+)
Jeroen Meekels: Maastricht University Medical Centre (MUMC+)
Burcu Yaldiz: Maastricht University Medical Centre (MUMC+)
Maartje Vorst: Maastricht University Medical Centre (MUMC+)
Bart Koning: Maastricht University Medical Centre (MUMC+)
Debby M. E. I. Hellebrekers: Maastricht University Medical Centre (MUMC+)
Servi J. C. Stevens: Maastricht University Medical Centre (MUMC+)
Su Ming Sun: Maastricht University Medical Centre (MUMC+)
Malou Heijligers: Maastricht University Medical Centre (MUMC+)
Sonja A. Munnik: Maastricht University Medical Centre (MUMC+)
Chris M. J. Uum: Maastricht University Medical Centre (MUMC+)
Jelle Achten: Maastricht University Medical Centre (MUMC+)
Lars Hamers: Maastricht University Medical Centre (MUMC+)
Marjan Naghdi: Maastricht University Medical Centre (MUMC+)
Lisenka E. L. M. Vissers: Radboud University Medical Center
Ron J. T. Golde: Maastricht University
Guido Wert: Maastricht University
Jos C. F. M. Dreesen: Maastricht University Medical Centre (MUMC+)
Christine Die-Smulders: Maastricht University Medical Centre (MUMC+)
Edith Coonen: Maastricht University Medical Centre (MUMC+)
Han G. Brunner: Maastricht University Medical Centre (MUMC+)
Arthur Wijngaard: Maastricht University Medical Centre (MUMC+)
Aimee D. C. Paulussen: Maastricht University Medical Centre (MUMC+)
Masoud Zamani Esteki: Maastricht University Medical Centre (MUMC+)

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51508-1

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