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Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation.

Bernkopf, M; Abdullah, UB; Bush, SJ; Wood, KA; Ghaffari, S; Giannoulatou, E; Koelling, N; Maher, GJ; Thibaut, LM; Williams, J; et al. Bernkopf, M; Abdullah, UB; Bush, SJ; Wood, KA; Ghaffari, S; Giannoulatou, E; Koelling, N; Maher, GJ; Thibaut, LM; Williams, J; Blair, EM; Kelly, FB; Bloss, A; Burkitt-Wright, E; Canham, N; Deng, AT; Dixit, A; Eason, J; Elmslie, F; Gardham, A; Hay, E; Holder, M; Homfray, T; Hurst, JA; Johnson, D; Jones, WD; Kini, U; Kivuva, E; Kumar, A; Lees, MM; Leitch, HG; Morton, JEV; Németh, AH; Ramachandrappa, S; Saunders, K; Shears, DJ; Side, L; Splitt, M; Stewart, A; Stewart, H; Suri, M; Clouston, P; Davies, RW; Wilkie, AOM; Goriely, A (2023) Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation. Nat Commun, 14 (1). p. 853. ISSN 2041-1723 https://doi.org/10.1038/s41467-023-36606-w
SGUL Authors: Elmslie, Frances Veryan

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Abstract

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.

Item Type: Article
Additional Information: 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/. © The Author(s) 2023
Keywords: Male, Pregnancy, Female, Humans, Child, Mutation, Parturition, Risk Assessment, Fathers, Germ Cells, Mosaicism, Pedigree, Germ-Line Mutation, Germ Cells, Humans, Risk Assessment, Pedigree, Fathers, Pregnancy, Parturition, Mutation, Mosaicism, Germ-Line Mutation, Child, Female, Male, Child, Fathers, Female, Germ Cells, Germ-Line Mutation, Humans, Male, Mosaicism, Mutation, Parturition, Pedigree, Pregnancy, Risk Assessment
Journal or Publication Title: Nat Commun
ISSN: 2041-1723
Language: eng
Dates:
DateEvent
15 February 2023Published
3 February 2023Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
219476/Z/19/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
102731/Z/13/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
G0902418Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_UP_1605/2Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
17/18/04NewLifeUNSPECIFIED
UNSPECIFIEDNational Institute for Health Research Oxford Biomedical Research CentreUNSPECIFIED
UNSPECIFIEDNIHR UK Rare Genetic Disease Research ConsortiumUNSPECIFIED
PubMed ID: 36792598
Web of Science ID: WOS:000940806000013
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/116866
Publisher's version: https://doi.org/10.1038/s41467-023-36606-w

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