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Germline genome editing (GGE) holds the potential to mitigate or even eliminate human heritable genetic disease, but also carries genuine risks if not appropriately regulated and performed. It also raises fears in some quarters of apocalyptic scenarios of designer babies that could radically change human reproduction. Clinical need and the availability of alternatives are key considerations in the ensuing ethical debate. Writing from the perspective of a fertility clinic, we offer a realistic projection of the demand for GGE. We lay out a framework proposing that GGE, hereditary genetic disorders, and in vitro fertilization are fundamentally entwined concepts. We note that the need for GGE to cure heritable genetic disease is typically grossly overestimated, mainly due to the underappreciated role of preimplantation genetic testing. However, we might still find applications for GGE in the correction of chromosomal abnormalities in early embryos, but techniques for that purpose do not yet exist.

Objective: To investigate the parameters of mosaicism and the biological mechanisms leading to healthy pregnancies from mosaic embryo transfers., Design: Prospective study., Setting: IVF center and associated research laboratory., Patient(s): Fifty-nine patients., Intervention(s): Embryos underwent blastocyst-stage preimplantation genetic testing for aneuploidy by next-generation sequencing. Trophectoderm biopsies containing 20%-80% abnormal cells were deemed mosaic, and corresponding blastocysts were transferred. Mosaic embryos donated to research were examined for karyotype concordance in multiple biopsies and assessed for cell proliferation and death by immunofluorescence and computational quantitation., Main Outcome Measure(s): Chemical start of pregnancy, implantation, fetal heartbeat, and birth., Result(s): Globally, mosaic embryos showed inferior clinical outcomes compared with euploid embryos. Aneuploid cell percentage in trophectoderm biopsies did not correlate with outcomes, but type of mosaicism did, as embryos with single mosaic segmental aneuploidies fared better than all other types. Mosaic blastocysts generated from oocytes retrieved at young maternal ages (≤34 years) showed better outcomes than those retrieved at older maternal ages. Mosaic embryos displayed low rates of karyotype concordance between multiple biopsies and showed significant elevation of cell proliferation and death compared with euploid embryos., Conclusion(s): After euploid embryos, mosaic embryos can be considered for transfer, prioritizing those of the single segmental mosaic type. If a patient has mosaic embryos available that were generated at different ages, preference should be given to those made at younger ages. Intrablastocyst karyotype discordance and differential cell proliferation and death might be reasons that embryos classified as mosaic can result in healthy pregnancies and babies., (Copyright © 2018 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To accurately determine mitochondrial DNA (mtDNA) levels in human blastocysts., Design: Retrospective analysis., Setting: IVF clinic., Patient(s): A total of 1,396 embryos derived from 259 patients., Intervention(s): Blastocyst-derived trophectoderm biopsies were tested by next-generation sequencing (NGS) and quantitative real-time polymerase chain reaction (qPCR)., Main Outcome Measure(s): For each sample the mtDNA value was divided by the nuclear DNA value, and the result was further subjected to mathematical analysis tailored to the genetic makeup of the source embryo., Result(s): On average the mathematical correction factor changed the conventionally determined mtDNA score of a given blastocyst via NGS by 1.43% ± 1.59% (n = 1,396), with maximal adjustments of 17.42%, and via qPCR by 1.33% ± 8.08% (n = 150), with maximal adjustments of 50.00%. Levels of mtDNA in euploid and aneuploid embryos showed a statistically insignificant difference by NGS (euploids n = 775, aneuploids n = 621) and by qPCR (euploids n = 100, aneuploids n = 50). Blastocysts derived from younger or older patients had comparable mtDNA levels by NGS ("young" age group n = 874, "advanced" age group n = 514) and by qPCR ("young" age group n = 92, "advanced" age group n = 58). Viable blastocysts did not contain significantly different mtDNA levels compared with unviable blastocysts when analyzed by NGS (implanted n = 101, nonimplanted n = 140) and by qPCR (implanted n = 49, nonimplanted n = 51)., Conclusion(s): We recommend implementation of the correction factor calculation to laboratories evaluating mtDNA levels in embryos by NGS or qPCR. When applied to our in-house data, the calculation reveals that overall levels of mtDNA are largely equal between blastocysts stratified by ploidy, age, or implantation potential., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)