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Clinical application of sequencing-based methods for parallel preimplantation genetic testing for mitochondrial DNA disease and aneuploidy.

Authors :
Spath K
Babariya D
Konstantinidis M
Lowndes J
Child T
Grifo JA
Poulton J
Wells D
Source :
Fertility and sterility [Fertil Steril] 2021 Jun; Vol. 115 (6), pp. 1521-1532. Date of Electronic Publication: 2021 Mar 19.
Publication Year :
2021

Abstract

Objective: To validate and apply a strategy permitting parallel preimplantation genetic testing (PGT) for mitochondrial DNA (mtDNA) disease and aneuploidy (PGT-A).<br />Design: Preclinical test validation and case reports.<br />Setting: Fertility centers. Diagnostics laboratory.<br />Patients: Four patients at risk of transmitting mtDNA disease caused by m.8993T>G (Patients A and B), m.10191T>G (Patient C), and m.3243A>G (Patient D). Patients A, B, and C had affected children. Patients A and D displayed somatic heteroplasmy for mtDNA mutations.<br />Interventions: Embryo biopsy, genetic testing, and uterine transfer of embryos predicted to be euploid and mutation-free.<br />Main Outcome Measures: Test accuracy, treatment outcomes, and mutation segregation.<br />Results: Accuracy of mtDNA mutation quantification was confirmed. The test was compatible with PGT-A, and half of the embryos tested were shown to be aneuploid (16/33). Mutations were detected in approximately 40% of embryo biopsies from Patients A and D (10/24) but in none from Patients B and C (n = 29). Patients B and C had healthy children following PGT and natural conception, respectively. The m.8993T>G mutation displayed skewed segregation, whereas m.3243A>G mutation levels were relatively low and potentially impacted embryo development.<br />Conclusions: Considering the high aneuploidy rate, strategies providing a combination of PGT for mtDNA disease and aneuploidy may be advantageous compared with approaches that consider only mtDNA. Heteroplasmic women had a higher incidence of affected embryos than those with undetectable somatic mutant mtDNA but were still able to produce mutation-free embryos. While not conclusive, the results are consistent with the existence of mutation-specific segregation mechanisms occurring during oogenesis and possibly embryogenesis.<br /> (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1556-5653
Volume :
115
Issue :
6
Database :
MEDLINE
Journal :
Fertility and sterility
Publication Type :
Academic Journal
Accession number :
33745725
Full Text :
https://doi.org/10.1016/j.fertnstert.2021.01.026