Cargando…
Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission
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...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255958/ https://www.ncbi.nlm.nih.gov/pubmed/35787314 http://dx.doi.org/10.7554/eLife.78459 |
_version_ | 1784741019087011840 |
---|---|
author | Breuss, Martin W Yang, Xiaoxu Stanley, Valentina McEvoy-Venneri, Jennifer Xu, Xin Morales, Arlene J Gleeson, Joseph G |
author_facet | Breuss, Martin W Yang, Xiaoxu Stanley, Valentina McEvoy-Venneri, Jennifer Xu, Xin Morales, Arlene J Gleeson, Joseph G |
author_sort | Breuss, Martin W |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9255958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-92559582022-07-06 Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission Breuss, Martin W Yang, Xiaoxu Stanley, Valentina McEvoy-Venneri, Jennifer Xu, Xin Morales, Arlene J Gleeson, Joseph G eLife Genetics and Genomics 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. eLife Sciences Publications, Ltd 2022-07-05 /pmc/articles/PMC9255958/ /pubmed/35787314 http://dx.doi.org/10.7554/eLife.78459 Text en © 2022, Breuss, Yang et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Genetics and Genomics Breuss, Martin W Yang, Xiaoxu Stanley, Valentina McEvoy-Venneri, Jennifer Xu, Xin Morales, Arlene J Gleeson, Joseph G Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
title | Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
title_full | Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
title_fullStr | Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
title_full_unstemmed | Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
title_short | Unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
title_sort | unbiased mosaic variant assessment in sperm: a cohort study to test predictability of transmission |
topic | Genetics and Genomics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9255958/ https://www.ncbi.nlm.nih.gov/pubmed/35787314 http://dx.doi.org/10.7554/eLife.78459 |
work_keys_str_mv | AT breussmartinw unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission AT yangxiaoxu unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission AT stanleyvalentina unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission AT mcevoyvennerijennifer unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission AT xuxin unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission AT moralesarlenej unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission AT gleesonjosephg unbiasedmosaicvariantassessmentinspermacohortstudytotestpredictabilityoftransmission |