Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data
dc.contributor.author | Wright, C | |
dc.contributor.author | Prigmore, E | |
dc.contributor.author | Rajan, D | |
dc.contributor.author | Handsaker, J | |
dc.contributor.author | McRae, J | |
dc.contributor.author | Kaplanis, J | |
dc.contributor.author | Fitzgerald, TW | |
dc.contributor.author | FitzPatrick, DR | |
dc.contributor.author | Firth, HV | |
dc.contributor.author | Hurles, ME | |
dc.date.accessioned | 2019-07-11T13:53:07Z | |
dc.date.issued | 2019-07-05 | |
dc.description.abstract | Mosaic genetic variants can have major clinical impact. We systematically analyse trio exome sequence data from 4,293 probands from the DDD Study with severe developmental disorders for pathogenic postzygotic mosaicism (PZM) in the child or a clinically-unaffected parent, and use ultrahigh-depth sequencing to validate candidate mosaic variants. We observe that levels of mosaicism for small genetic variants are usually equivalent in both saliva and blood and ~3% of causative de novo mutations exhibit PZM; this is an important observation, as the sibling recurrence risk is extremely low. We identify parental PZM in 21 trios (0.5% of trios), resulting in a substantially increased sibling recurrence risk in future pregnancies. Together, these forms of mosaicism account for 40 (1%) diagnoses in our cohort. Likely child-PZM mutations occur equally on both parental haplotypes, and the penetrance of detectable mosaic pathogenic variants overall is likely to be less than half that of constitutive variants. | en_GB |
dc.description.sponsorship | Health Innovation Challenge Fund | en_GB |
dc.description.sponsorship | Wellcome Sanger Institute | en_GB |
dc.description.sponsorship | Medical Research Council (MRC) | en_GB |
dc.identifier.citation | Vol. 10, article 2985 | en_GB |
dc.identifier.doi | 10.1038/s41467-019-11059-2 | |
dc.identifier.grantnumber | HICF-1009–003 | en_GB |
dc.identifier.grantnumber | WT098051 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/37957 | |
dc.language.iso | en | en_GB |
dc.publisher | Nature Research | en_GB |
dc.rights | © The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. | en_GB |
dc.title | Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2019-07-11T13:53:07Z | |
dc.identifier.issn | 2041-1723 | |
dc.description | This is the final version. Available on open access from Nature Research via the DOI in this record | en_GB |
dc.identifier.journal | Nature Communications | en_GB |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/. | en_GB |
dcterms.dateAccepted | 2019-06-12 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2019-07-05 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2019-07-11T09:17:08Z | |
refterms.versionFCD | EVoR | |
refterms.dateFOA | 2019-07-11T13:53:17Z | |
refterms.panel | A | en_GB |
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Except where otherwise noted, this item's licence is described as © The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.