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Lookup NU author(s): Dr Louise Hyslop, Dr Magomet AushevORCiD, Jordan Marley, Dr Yuko Takeda, Dr Angela Pyle, Catherine Feeney, Sarah Smith, Dr Charlotte Alston, Lisa Lister, Dr Nilendran Prathalingam, Dr Matthew Prior, Professor Alison Murdoch, Emeritus Professor Doug Turnbull, Professor Gavin HudsonORCiD, Dr Meenakshi Choudhary, Professor Robert TaylorORCiD, Dr Jane Stewart, Professor Bobby McFarlandORCiD, Professor Mary Herbert
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright © 2025 Massachusetts Medical Society. BACKGROUND: Children born to women who carry pathogenic variants in mitochondrial DNA (mtDNA) are at risk for a range of clinical syndromes collectively known as mtDNA disease. Mitochondrial donation by pronuclear transfer involves transplantation of nuclear genome from a fertilized egg from the affected woman to an enucleated fertilized egg donated by an unaffected woman. Thus, pronuclear transfer offers affected women the potential to have a genetically related child with a reduced risk of mtDNA disease. METHODS: We offered mitochondrial donation (by pronuclear transfer) or preimplantation genetic testing (PGT) to a series of women with pathogenic mtDNA variants who sought to reduce the transmission of these variants to their children. Patients with heteroplasmy (variants present in a proportion of copies of mtDNA) were offered PGT, and patients with homoplasmy (variants present in all copies of mtDNA) or elevated heteroplasmy were offered pronuclear transfer. RESULTS: Clinical pregnancies were confirmed in 8 of 22 patients (36%) and 16 of 39 patients (41%) who underwent an intracytoplasmic sperm injection procedure for pronuclear transfer or for PGT, respectively. Pronuclear transfer resulted in 8 live births and 1 ongoing pregnancy. PGT resulted in 18 live births. Heteroplasmy levels in the blood of the 8 infants whose mothers underwent pronuclear transfer ranged from undetectable to 16%. Levels of the maternal pathogenic mtDNA variant were 95 to 100% lower in 6 newborns and 77 to 88% lower in 2 newborns than in the corresponding enucleated zygotes. Heteroplasmy levels were known for 10 of the 18 infants whose mothers underwent PGT and ranged from undetectable to 7%. CONCLUSIONS: We found that mitochondrial donation through pronuclear transfer was compatible with human embryo viability. An integrated program involving pronuclear transfer and PGT was effective in reducing the transmission of homoplasmic and heteroplasmic pathogenic mtDNA variants. (Funded by NHS England and others.).
Author(s): Hyslop LA, Blakely EL, Aushev M, Marley J, Takeda Y, Pyle A, Moody E, Feeney C, Dutton J, Shaw C, Smith SJ, Craig K, Alston CL, Lister L, Endacott K, Byerley S, McDermott H, Wilson K, Botham L, Matthew B, Prathalingam N, Prior M, Murdoch A, Turnbull DM, Hudson G, Choudhary M, Taylor RW, Pillai RN, Stewart JA, McFarland R, Herbert M
Publication type: Article
Publication status: Published
Journal: New England Journal of Medicine
Year: 2025
Volume: 393
Issue: 5
Pages: 438-449
Print publication date: 31/07/2025
Online publication date: 16/07/2025
Acceptance date: 02/04/2018
Date deposited: 16/10/2025
ISSN (print): 0028-4793
ISSN (electronic): 1533-4406
Publisher: Massachusetts Medical Society
URL: https://doi.org/10.1056/NEJMoa2415539
DOI: 10.1056/NEJMoa2415539
PubMed id: 40673696
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