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

Lookup NU author(s): Dr Miranda Splitt



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023. The Author(s). 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.

Publication metadata

Author(s): 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, Nemeth 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

Publication type: Article

Publication status: Published

Journal: Nature communications

Year: 2023

Volume: 14

Issue: 1

Online publication date: 15/02/2023

Acceptance date: 03/02/2023

Date deposited: 02/03/2023

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/s41467-023-36606-w

PubMed id: 36792598


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