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© 2022, Breuss, Yang et al. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background:

De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring.

Methods:

As a cohort study, in three independent couples undergoing in vitro fertilization, we first identified male gonadal mosaicism through deep whole genome sequencing. We then confirmed variants and assessed their transmission to preimplantation blastocysts (32 total) through targeted ultra-deep genotyping.

Results:

Across 55 gonadal mosaic variants, 15 were transmitted to blastocysts for a total of 19 transmission events. This represented an overall predictable but slight undertransmission based upon the measured mutational abundance in sperm. We replicated this conclusion in an independent, previously published family-based cohort.

Conclusions:

Unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations. This—in turn—could help to reduce their impact on miscarriages and pediatric disease.

Funding:

No external funding was received for this work.

Details

Title
Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission
Author
Breuss, Martin W; Yang, Xiaoxu; Stanley, Valentina; McEvoy-Venneri, Jennifer; Xu, Xin; Morales, Arlene J; Gleeson, Joseph G
University/institution
U.S. National Institutes of Health/National Library of Medicine
Publication year
2022
Publication date
2022
Publisher
eLife Sciences Publications Ltd.
e-ISSN
2050084X
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2696818810
Copyright
© 2022, Breuss, Yang et al. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.