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

Humans Preimplantation Diagnosis / methods Whole Genome Sequencing / methods Female Fertilization in Vitro / methods Genetic Testing / methods Aneuploidy Pregnancy DNA, Mitochondrial / genetics High-Throughput Nucleotide Sequencing / methods Genome, Human / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
02 Sep 2024

Historique:

received: 08 12 2023

accepted: 08 08 2024

medline: 3 9 2024

pubmed: 3 9 2024

entrez: 2 9 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-51508-1 PMID: 39223156

pubmed: 39223156

doi: 10.1038/s41467-024-51508-1

pii: 10.1038/s41467-024-51508-1

doi:

Substances chimiques

DNA, Mitochondrial 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

7164

Subventions

Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)

ID : EU952516

Informations de copyright

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