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

Bernkopf, Marie and Abdullah, Ummi B. and Bush, Stephen J. and Wood, Katherine A. and Ghaffari, Sahar and Giannoulatou, Eleni and Koelling, Nils and Maher, Geoffrey J. and Thibaut, Loïc M. and Williams, Jonathan and Blair, Edward M. and Kelly, Fiona Blanco and Bloss, Angela and Burkitt-Wright, Emma and Canham, Natalie and Deng, Alexander T. and Dixit, Abhijit and Eason, Jacqueline and Elmslie, Frances and Gardham, Alice and Hay, Eleanor and Holder, Muriel and Homfray, Tessa and Hurst, Jane A. and Johnson, Diana and Jones, Wendy D. and Kini, Usha and Kivuva, Emma and Kumar, Ajith and Lees, Melissa M. and Leitch, Harry G. and Morton, Jenny E. V. and Németh, Andrea H. and Ramachandrappa, Shwetha and Saunders, Katherine and Shears, Deborah J. and Side, Lucy and Splitt, Miranda and Stewart, Alison and Stewart, Helen and Suri, Mohnish and Clouston, Penny and Davies, Robert W. and Wilkie, Andrew O. M. and Goriely, Anne (2023) Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation. Nature Communications, 14 (1). ISSN 2041-1723

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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
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 06 Mar 2023 04:28
Last Modified: 10 Mar 2023 06:28

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