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

Marie Bernkopf, Ummi B. Abdullah, Stephen J. Bush, Katherine A. Wood, Sahar Ghaffari, Eleni Giannoulatou, Nils Koelling, Geoffrey J. Maher, Loïc M. Thibaut, Jonathan Williams, Edward M. Blair, Fiona Blanco Kelly, Angela Bloss, Emma Burkitt-Wright, Natalie Canham, Alexander T. Deng, Abhijit Dixit, Jacqueline Eason, Frances Elmslie, Alice Gardham, Eleanor Hay, Muriel Holder, Tessa Homfray, Jane A. Hurst, Diana Johnson, Wendy D. Jones, Usha Kini, Emma Kivuva, Ajith Kumar, Melissa M. Lees, Harry G. Leitch, Jenny E. V. Morton, Andrea H. Németh, Shwetha Ramachandrappa, Katherine Saunders, Deborah J. Shears, Lucy Side, Miranda Splitt, Alison Stewart, Helen Stewart, Mohnish Suri, Penny Clouston, Robert W. Davies, Andrew O. M. Wilkie and Anne Goriely ()
Additional contact information
Marie Bernkopf: University of Oxford
Ummi B. Abdullah: University of Oxford
Stephen J. Bush: University of Oxford
Katherine A. Wood: University of Oxford
Sahar Ghaffari: University of Oxford
Eleni Giannoulatou: Victor Chang Cardiac Research Institute
Nils Koelling: University of Oxford
Geoffrey J. Maher: University of Oxford
Loïc M. Thibaut: Garvan Institute of Medical Research, UNSW Sydney
Jonathan Williams: Oxford University Hospitals NHS Foundation Trust
Edward M. Blair: NIHR Oxford Biomedical Research Centre
Fiona Blanco Kelly: Oxford University Hospitals NHS Foundation Trust
Angela Bloss: Oxford University Hospitals NHS Foundation Trust
Emma Burkitt-Wright: Manchester University NHS Foundation Trust
Natalie Canham: Liverpool Women’s NHS Foundation Trust
Alexander T. Deng: Guy’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust
Abhijit Dixit: Nottingham University Hospitals NHS Trust
Jacqueline Eason: Nottingham University Hospitals NHS Trust
Frances Elmslie: St George’s University Hospitals NHS Foundation Trust
Alice Gardham: London North West University Healthcare NHS Trust, Northwick Park Hospital
Eleanor Hay: Great Ormond Street Hospital NHS Foundation Trust
Muriel Holder: Guy’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust
Tessa Homfray: St George’s University Hospitals NHS Foundation Trust
Jane A. Hurst: Great Ormond Street Hospital NHS Foundation Trust
Diana Johnson: Sheffield Children’s NHS Foundation Trust
Wendy D. Jones: Great Ormond Street Hospital NHS Foundation Trust
Usha Kini: NIHR Oxford Biomedical Research Centre
Emma Kivuva: Royal Devon University Healthcare NHS Foundation Trust
Ajith Kumar: Great Ormond Street Hospital NHS Foundation Trust
Melissa M. Lees: Great Ormond Street Hospital NHS Foundation Trust
Harry G. Leitch: Nottingham University Hospitals NHS Trust
Jenny E. V. Morton: Birmingham Women’s and Children’s Hospitals NHS Foundation Trust
Andrea H. Németh: Oxford University Hospitals NHS Foundation Trust
Shwetha Ramachandrappa: Guy’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust
Katherine Saunders: Oxford University Hospitals NHS Foundation Trust
Deborah J. Shears: Oxford University Hospitals NHS Foundation Trust
Lucy Side: University Hospital Southampton, Princess Anne Hospital
Miranda Splitt: The Newcastle upon Tyne Hospitals NHS Foundation Trust
Alison Stewart: Sheffield Children’s NHS Foundation Trust
Helen Stewart: Oxford University Hospitals NHS Foundation Trust
Mohnish Suri: Nottingham University Hospitals NHS Trust
Penny Clouston: Oxford University Hospitals NHS Foundation Trust
Robert W. Davies: University of Oxford
Andrew O. M. Wilkie: University of Oxford
Anne Goriely: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36606-w

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